Liquid oral formulations for pde v inhibitors

ABSTRACT

The present disclosure is directed to pharmaceutical compositions comprising a PDE V inhibitor and one or more pharmaceutical excipients or additives wherein the pharmaceutical compositions are in the form of liquid pharmaceutical compositions. The pharmaceutical compositions of the present disclosure are useful for the treatment of diseases or conditions which are treatable by administration of PDE V inhibitor drug such as pulmonary arterial hypertension, erectile dysfunction, etc.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/957,894, filed on Jun. 25, 2020 as a National Stage Application ofPCT/IB2018/001462, filed on Dec. 24, 2018, which claims priority toIndian Patent Application No. IN201721046640, filed on Dec. 26, 2017,and Indian Patent Application No. IN201821012438, filed on Apr. 2, 2018,where each application is incorporated herein by reference.

FIELD

The present disclosure relates, in general to the pharmaceutical field,and more precisely it relates to the pharmaceutical compositionscomprising PDE V inhibitors. In particular, the present disclosurerelates to the liquid compositions comprising PDE V inhibitors e.g.sildenafil, tadalafil, or sildenafil citrate. The pharmaceuticalcompositions disclosed herein may be useful for treating pulmonaryarterial hypertension and/or diseases in which PDE V inhibitors havebeen found as effective therapy for, for example, male erectiledysfunction.

SUMMARY

Embodiments herein are directed to liquid oral formulations of PDE Vinhibitors. In some embodiments, a liquid pharmaceutical composition ofa PDE V inhibitor drug comprises a PDE V inhibitor drug or a derivativethereof and a wetting agent, wherein the pH of the pharmaceuticalcomposition is about 4 to about 8. In some embodiments, thepharmaceutical composition further comprises one or morepharmaceutically acceptable excipients selected from the groupconsisting of vehicles, solvents/co-solvents, solubilizers, solubilityenhancing agents, viscosity modifying agents, permeation/penetrationenhancers, tonicity agents, mucoadhesives, bulking agents/auxiliarysuspending agents, chelating agents, wetting agents, anti-foamingagents, anti-caking agents, stabilizing agents, anti-oxidants, pHmodifying agents and/or pH adjusting agents, surfactants, preservatives,sweetening agents, flavoring agents and coloring agents and combinationthereof. In some embodiments, the one or more pharmaceuticallyacceptable excipients is a buffering agent. In some embodiments, thepharmaceutical composition is a suspension, wherein the wetting agent isglycerin. In some embodiments, the glycerin to buffering agent ratio inthe pharmaceutical composition is about 40:60. In some embodiments, thebuffering agent is in an amount suitable to make the composition pHabout 4 to about 8. In some embodiments, the liquid pharmaceuticalcomposition may be in the form of a solution or a suspension. In someembodiments, the pharmaceutical composition is a suspension furthercomprising a viscosity modifying agent.

In some embodiments, the PDE V inhibitor drug is selected from the groupcomprising of Avanafil, AWD-12-250, BF/GP-385, BMS-22313, BMS-341400,CP-248, CP-461, DA-8159, Dasantafil, DMPPO, E-4021, E-8010, EMD-82639,EMR-62203, Exisulind, FR-181074, FR-226807, FR-229934, GF-248, KF-31327,KT-734, LAS-34 179, Lusupultide, MJ-12504, NCX-91 1, NM-702, OPC-35564,OSI-461, QAD-171A, Roflumilast, SB-96231, SCH-46642, SCH-51866,SCH-59498, Sildenafil, Sildenafil citrate, SK-350, SK-3530, SKF-96231,Sophoflavescenol, SR-265579, T-0156, T-1032, Tadalafil, UK-1 14502, UK-114542, UK-357903, UK-369003, UK-371800, UK-83405, Vardenafil, WIN-65579,WS-63967, YC-1 and Zaprinast, or pharmaceutically acceptable salts,chemical derivatives such as polymorphs, solvates, hydrates, anhydrousforms, amorphous forms, prodrugs, racemic mixtures or pure forms,chelates, and complexes thereof. In some embodiments, the PDE Vinhibitor drug is sildenafil. In some embodiments, the PDE V inhibitordrug is sildenafil citrate. In some embodiments, the PDE V inhibitordrug is tadalafil.

Some embodiments are directed to the use of a liquid pharmaceuticalcomposition according to an embodiment herein in the treatment of atleast one disease or condition selected from the group comprising ofhypertension, pulmonary hypertension, arterial hypertension, pulmonaryarterial hypertension, erectile dysfunction, cirrhosis, solid tumor,heart failure, cerebral vasospasm, arthritis, rheumatoid arthritis,atherosclerosis, congenital heart diseases, parkinsons disease, neonatalencephalopathy, pre-eclampsia, prostate cancer, pancreatic cancer,hepatic encephalopathy, aortic stenosis, cystic fibrosis, peripheralarterial occlusive disease, sickle cell disease, priapism, age-relatedmacular degeneration, schizophrenia, bronchopulmonary dysplasia,impotence, lymphangioma, dysmenorrhea, urinary incontinence, chronicobstructive pulmonary disease, lymphatic malformations, duchennemuscular dystrophy, becker muscular dystrophy, pulmonary fibrosis,nontuberculous mycobacterial infection, idiopathic pulmonary fibrosis,raynaud's phenomenon, prostatic hyperplasia, benign prostatichyperplasia Waldenstrom's macroglobulinemia and any combination thereof.

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, formulations, compositions, or methodologies described, asthese may vary. It is also to be understood that the terminology used inthe description is for the purpose of describing the particular versionsor embodiments only, and is not intended to limit the scope ofembodiments herein which will be limited only by the appended claims.Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments of embodiments herein, the preferred methods, devices, andmaterials are now described. All publications mentioned herein areincorporated by reference in their entirety. Nothing herein is to beconstrued as an admission that embodiments herein is not entitled toantedate such disclosure by virtue of prior invention.

Definitions

It must also be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “surfactant” is a reference to one or more surfactants and equivalentsthereof known to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a patient whereby the therapeutic positivelyimpacts the tissue to which it is targeted. Thus, as used herein, theterm “administering”, when used in conjunction with an activepharmaceutical ingredient, can include, but is not limited to, providingthe active pharmaceutical ingredient into or onto the target tissue;providing the active pharmaceutical ingredient systemically to a patientby, e.g., intravenous injection whereby the therapeutic reaches thetarget tissue; providing the active pharmaceutical ingredient in theform of the encoding sequence thereof to the target tissue.“Administering” a composition may be accomplished by injection, topicaladministration, orally, or by either method in combination with otherknown techniques. In some embodiments, administering is through an oralroute of administration.

The term “subject” as used herein includes, but is not limited to,humans and non-human vertebrates such as wild, domestic, and farmanimals. In certain embodiments, the subject described herein is ananimal. In certain embodiments, the subject is a mammal. In certainembodiments, the subject is a human. In certain embodiments, the subjectis a non-human animal. In certain embodiments, the subject is anon-human mammal. In certain embodiments, the subject is a domesticatedanimal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a companion animal such as a dog or cat. Incertain embodiments, the subject is a livestock animal such as a cow,pig, horse, sheep, or goat. In certain embodiments, the subject is a zooanimal. In another embodiment, the subject is a research animal such asa rodent, dog, or non-human primate. In certain embodiments, the subjectis a non-human transgenic animal such as a transgenic mouse ortransgenic pig.

The term “improve” is used to convey that the compounds of embodimentsherein change either the appearance, form, characteristics and/or thephysical attributes of the tissue to which it is being provided, appliedor administered. In some embodiments, the pharmaceutical compositions ofembodiments herein comprising sildenafil for male erectile dysfunction.

The term “inhibit” includes the administration of a compound ofembodiments herein to prevent the onset of the symptoms, alleviating thesymptoms, or eliminating the disease, condition or disorder. In someembodiments, the pharmaceutical compositions of embodiments hereincomprising a sildenafil are used to inhibit symptoms of pulmonaryarterial hypertension.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “pharmaceutically acceptable excipients” as used herein refersto such pharmaceutically acceptable excipients which are known to thoseskilled in the art for the purposes of preparing liquid pharmaceuticalcompositions of the present disclosure. Such pharmaceutically acceptableexcipients, without limitation include, vehicles, solvents/co-solvents,solubilizers, solubility enhancing agents, tonicity agents,permeation/penetration enhancers, mucoadhesives, viscosity modifyingagents, bulking agents/auxiliary suspending agents, wetting agents,anti-foaming agents, anti-caking agents, stabilizing agents,anti-oxidants, chelating agents, buffering agents/pH modifying agents/pHadjusting agents, surfactants, preservatives, sweetening agents,flavoring agents and the like or any combination thereof. Suchpharmaceutically acceptable excipients can be used in an amount whichprovides the liquid pharmaceutical compositions of the presentdisclosure desired property for which they are intended or desired touse.

As used herein, the terms “stable” or “stability” encompass anycharacteristic of the liquid compositions which may be affected bystorage conditions including, without limitation, potency, totalimpurities, degradation products, specific optical rotation, opticalpurity, water content, appearance, viscosity, sterility, and colour andclarity. The storage conditions which may affect stability include, forexample, duration of storage, temperature, humidity, and/or lightexposure.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, inhibit, ameliorate, prevent or improve an unwanted condition ordisease of a patient. In part, the pharmaceutical compositions ofembodiments herein are directed to the treatment of male erectiledysfunction.

A “therapeutically effective amount” or “effective amount” of acomposition is a predetermined amount calculated to achieve the desiredeffect. The activity contemplated by the present methods includes bothmedical therapeutic and/or prophylactic treatment, as appropriate. Thespecific dose of a compound administered according to this invention toobtain therapeutic and/or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration, concomitant therapies and the condition being treated.However, it will be understood that the effective amount administeredwill be determined by the physician in the light of the relevantcircumstances including the condition to be treated, the choice ofcompound to be administered, and the chosen route of administration, andtherefore the above dosage ranges are not intended to limit the scope ofembodiments herein in any way. A therapeutically effective amount of acompound of this disclosure is typically an amount such that when it isadministered in a physiologically tolerable excipient composition, it issufficient to achieve an effective systemic concentration or localconcentration in the tissue.

The terms “treat,” “treated,” or “treating,” as used herein, refers toboth therapeutic treatment and prophylactic or preventative measures,wherein the object is to inhibit, prevent or slow down (lessen) anundesired physiological condition, disorder or disease, or to improve,inhibit, or otherwise obtain beneficial or desired clinical results. Forthe purposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, improvement or alleviation of symptoms;diminishment of the extent of the condition, disorder or disease;stabilization (i.e., not worsening) of the state of the condition,disorder or disease; delay in onset or slowing of the progression of thecondition, disorder or disease; amelioration of the condition, disorderor disease state; and remission (whether partial or total), whetherdetectable or undetectable, or enhancement or improvement of thecondition, disorder or disease. Treatment includes eliciting aclinically significant response without excessive levels of sideeffects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment.

As used herein, the term “a derivative thereof” refers to a saltthereof, a pharmaceutically acceptable salt thereof, an ester thereof, afree acid form thereof, a free base form thereof, a solvate thereof, adeuterated derivative thereof, a hydrate thereof, an N-oxide thereof, aclathrate thereof, a prodrug thereof, a polymorph thereof, astereoisomer thereof, a geometric isomer thereof, a tautomer thereof, amixture of tautomers thereof, an enantiomer thereof, a diastereomerthereof, a racemate thereof, a mixture of stereoisomers thereof, anisotope thereof (e.g., tritium, deuterium), or a combination thereof. Insome embodiments, the active pharmaceutical ingredient may beadministered as a derivative thereof. In some embodiments, reference toa derivative, e.g. a salt thereof, shall be interchangeable with theactive pharmaceutical ingredient or any other derivative thereof. Forexample, unless otherwise stated, sildenafil and sildenafil citrate maybe used interchangeably herein.

In embodiments or claims where the term “comprising” is used as thetransition phrase, such embodiments can also be envisioned withreplacement of the term “comprising” with the terms “consisting of or“consisting essentially of.”

As used herein, the term “consists of or “consisting of means that thecomposition, formulation or the method includes only the elements,steps, or ingredients specifically recited in the particular claimedembodiment or claim.

As used herein, the term “consisting essentially of or “consistsessentially of means that the composition, formulation or the methodincludes only the elements, steps or ingredients specifically recited inthe particular claimed embodiment or claim and may optionally includeadditional elements, steps or ingredients that do not materially affectthe basic and novel characteristics of the particular embodiment orclaim. For example, the only active pharmaceutical ingredient(s) in theformulation or method that treats the specified condition (e.g.seizures) is the specifically recited therapeutic(s) in the particularembodiment or claim.

PDE V Inhibitors

A phosphodiesterase type V inhibitor (PDE V inhibitor) is a drug used toblock the degradative action of cGMP-specific phosphodiesterase type V(PDE V) on cyclic GMP in the smooth muscle cells lining the bloodvessels supplying the corpus cavernosum of the penis. These drugs areused in the treatment of erectile dysfunction and were the firsteffective oral treatment available for the condition. Because PDE V isalso present in the arterial wall of smooth muscle within the lungs, PDEV inhibitors have also been explored for the treatment of pulmonaryarterial hypertension, a disease in which blood vessels in the lungsbecome overloaded with fluid, usually as a result of failure of theright ventricle of the heart.

Sildenafil is a drug belonging to the group of selective inhibitors ofphosphodiesterase-V (PDE V), an enzyme that is responsible for thedegradation of cyclic guanosine monophosphate (cGMP), such that theSildenafil promotes an increase in cGMP levels, which in turn promotesthe relaxation of smooth muscle tissue.

The PDE V enzyme is present, for example, in the pulmonary vasculature,such that Sildenafil induces an increase in cGMP in the cells of thelungs' smooth muscle vasculature, which has a therapeutic application inpatients affected by pulmonary hypertension due to its vasodilatoryeffect on the pulmonary vascular bed and on systemic circulation.

This enzyme is also present in the corpora cavernosa in the penis,Sildenafil is, therefore, used in the treatment of erectile dysfunction,as an increase in cGMP levels causes the relaxation of the smoothmuscles in the erectile tissue of these corpora cavernosa, allowingblood to flow into its interior, thereby promoting an erection.

The USFDA approved Sildenafil for the treatment of Pulmonary ArterialHypertension (PAH) in 2005. It is marketed for PAH as REVATIO®. In 2009,USFDA also approved Tadalafil, another PDE V inhibitor, marketed underthe name ADCIRCA®. PDE V inhibitors are believed to increase pulmonaryartery vasodilation, and inhibit vascular remodeling, thus loweringpulmonary arterial pressure and pulmonary vascular resistance.

REVATIO® manufactured by Pfizer Pharmaceuticals is most often suppliedas 20 mg tablets to be taken 3 times daily. Sildenafil citrate is oftenlabeled with the amount of Sildenafil so that the actual amount ofSildenafil citrate is about 30% more than the dosage/tablet indicated onthe label.

REVATIO® is also available in injectable form as a clear colorless,sterile, and ready to use solution containing 10 mg of Sildenafilcitrate per 12.5 ml of solution. Each ml of solution contains 1.124 mgsildenafil citrate, 50.5 mg dextrose and water for injection. Theinjectable form of REVATIO® is most often administered intravenously.This route of administration is practical in a hospital setting butimpractical outside a 20 hospital or clinic setting.

REVATIO® (Sildenafil citrate) is also available as powder for oralsuspension (POS) at a concentration of 10 mg/ml. REVATIO® POS issupplied by Pfizer to be made up into an oral suspension. Additionalingredients in the POS include colloidal silicon dioxide, sucralose,sorbitol, sodium benzoate, sodium citrate, flavor and xanthan gum. Theactive ingredient in suspension has a slower absorption rate than wouldbe expected for a solution with a similar concentration. In addition,the presence of some of the additional ingredients makes this productdifficult to tolerate for people with known sensitivities to theseingredients.

Whether provided as tablets or oral suspension, Sildenafil citrateexhibits an absolute bioavailability of about 41% and is reported toresult in maximum observed plasma concentrations within 30 to 120minutes following oral dosing in a fasted state. The rate of absorptionis reportedly reduced if taken with a high fat meal.

According to the US package insert for VIAGRA®, solubility of Sildenafilcitrate in water is 3.5 mg/ml. The EMEA CHMP Assessment Report forVizarsin (International Nonproprietary Name: Sildenafil) indicates thatit is insoluble in ethanol, chloroform and acetone but soluble inmethanol and dimethylsulfoxide (DMSO). The Jordanian PharmaceuticalManufacturing Co. reports that Sildenafil citrate is about 3.5 timesless soluble in ethanol than in water (˜1 mg/ml). The low watersolubility of Sildenafil citrate and/or its high pre-systemicelimination each independently contribute to its low oralbioavailability.

Tadalafil is an active ingredient of an erectile dysfunction medicamentthat is well-known under the trade name CIALIS®. Tadalafil is aselective and reversible inhibitor for cGMP-specific PDE V(phosphodiesterase type V). When nitrogen oxide is locally released dueto sexual arousal, the level of cGMP is increased in the corpuscavernosum due to the inhibition of PDE V by Tadalafil. When the levelof cGMP is increased in this way, smooth muscle relaxation and bloodinflow to the penile tissue may result, thus causing an erection.Tadalafil has also been approved by the USFDA for the treatment ofpulmonary arterial hypertension to improve exercise ability under thetrade name of ADCIRCA®.

When tadalafil is absorbed via oral administration, the average timerequired to reach the maximum blood concentration (Cmax) is reported tobe 2 hours. Thereby, Tadalafil is recommended to be taken at least 30min prior to a sexual act. However, waiting 30 min before sex isregarded as very awkward to users.

Also, tadalafil exhibits a very low bioavailability of 20.5% whenmeasured using rats upon intravenous administration. Such a lowbioavailability results from very low solubility of Tadalafil, andconcretely, Tadalafil merely has a water solubility of about 2 μg/mL.

Because of the low solubility of tadalafil, tadalafil is substantially apoorly soluble drug. Since a drug that is orally administered isabsorbed only in an amount that can be dissolved in gastrointestinaltract fluids, the bioavailability of tadalafil is considerably low.

Children generally reject taking medicine which does not have afavorable shape, taste, flavor, etc. However, if a child who needs totake a medicine, rejects taking it, he might never recover from hiscondition. When a child is unable to take medicine orally, it isintravenously administered, and he and his caregivers then mayexperience stress. Syrups and suspensions are considered as favorabletypes of dosage forms in which to orally administer medicine to infantsand children. However, they may have disadvantages such as solubility, abad taste, portability problems or required refrigerator storage. WorldHealth Organization (WHO) currently favors that infants and children betreated with oral solid medicines. New oral solid tablets, such as amini-tablet, instead of liquid medicines are proposed for this group,however, there are a few reports that mini-tablets are suitable forinfants and children. Palatability is one of the main elements ofpatient acceptability of an oral pediatric medicine. Palatability isdefined as the overall appreciation of an oral medicinal product inrelation to its smell, taste, aftertaste and feeling in the mouth.Design of the formulation of an oral pediatric medicine should beconsidered together with its palatability.

Compared to conventional tablets and capsules, oral liquid dosage formsincluding solutions, syrups, suspensions, elixirs, and concentratesoffer unique advantages to many patients. For example, liquids mayprovide better patient compliance for those with swallowing difficultiesand better dosage control versus a fixed tablet dose. Hence, liquiddosage forms are generally formulated for use in geriatric and pediatricpatients. However, there are also a number of “challenges” surroundingthe formulation and development of these forms.

Oral liquids are formulated as solutions, suspensions and emulsionsdepending on the nature of the active ingredient particularly solubilityand stability. They are also designed as ready to use liquids andpowders for reconstitution into liquid orals like syrups, solutions,suspensions and emulsions. Liquid formulation needs various excipientsincluding vehicle, solubilizer, stabilizer, and viscosity builder,preservative and off course sweeteners, color and flavor. The selectionof these excipients is of major concern to design stable, effective andpalatable oral liquid formulation.

Characteristics of active drug are of major concern in developing anoral liquid dosage formulation. The major challenges in developing oralliquid dosage forms are (i) the stability of a drug in solution, (ii)the solubility of a drug at the required level, and (iii) an acceptabletaste. It is the effective use of excipients, which allows formulatorsovercome these challenges. Additionally, an excipient's compatibilitywith a drug in the solid state cannot infer the same compatibility insolution.

The decision to develop a solution, syrup or a suspension of a drug isinfluenced by many factors like solubility and the desired releaseprofile of the drug and properties of the base vehicle like surfacetension, viscosity, boiling point, and specific heat of solution, all ofwhich may be affected in various ways. In case of clear liquids, lack ofsolubility of the drug in the base vehicle may demand the need formiscible co-solvents. Similarly, a miscible solvent may be needed todecrease the solubility of the drug in a primary vehicle in formulatinga suspension.

The therapeutic utility of drugs involves the application of dosageforms/delivery systems, which serve as carrier systems together withseveral excipients to deliver the active therapeutic agent to the siteof action. Suspensions are an important class of pharmaceutical dosageforms that may be given by many routes, including oral, topical,parenteral, and also used in the eye for ophthalmic purposes.Surprisingly, large proportions of new drug candidates that are emergingare predominantly water insoluble and, therefore, demonstrate poorbioavailability in the solution dosage form. While suspensions present aviable formulation option for many drugs, particularly for waterinsoluble, hydrophobic drug substances, there are certain criteria thata well-formulated suspension should meet.

The suspension dosage form has long been used for poorly soluble activeingredients for various therapeutic indications. Development of stablesuspensions over the shelf life of the drug product continues to be achallenge on many fronts. Drugs from suspension formulations typicallyexhibit an improved bioavailability when compared to the same drugformulated as a tablet or capsule.

A good understanding of the fundamentals of dispersion systems isessential in the development of a suitable pharmaceutical suspension.The development of a suspension dosage form follows a very complicatedpath. The selection of the proper excipients (surfactants, viscosityimparting agents etc.) is important. The particle size distribution inthe finished drug product dosage form is a critical parameter thatsignificantly impacts the bioavailability and pharmacokinetics of theproduct.

Suspensions are an important class of pharmaceutical dosage forms. Theadvantages of suspension dosage forms include effective dispensing ofhydrophobic drugs; avoidance of the use of co-solvents; masking ofunpleasant taste of certain ingredients; offering resistance todegradation of drugs due to hydrolysis, oxidation or microbial activity;easy swallowing for young or elderly patients; and efficientintramuscular depot therapy. In addition, when compared to solutiondosage forms, relatively higher concentration of drugs can beincorporated into suspension products. To date, numerous theories havebeen introduced and successfully used to explain the unique behavior ofsuspension preparations.

Ready to use liquid compositions of PDE V inhibitors are not muchexplored in the prior art. REVATIO® is a powder for oral suspension(POS) and not a ready to use liquid composition. REVATIO® POS requiresthat it be mixed with water in order to prepare a suspension before use.Reconstitution of the powder for oral suspension comprises followingsteps (retrieved from the USFDA prescribing information of REVATIO®;www.accessdata.fda.gov/drugsatfda_docs/label/2017/203l09s01l,022473s0l1,021845s020lbl.pdf):

-   -   1. Tap the bottle to release the powder.    -   2. Remove the cap.    -   3. Accurately measure out 60 mL of water and pour the water into        the bottle.    -   4. Replace the cap and shake the bottle vigorously for a minimum        of 30 seconds.    -   5. Remove the cap.    -   6. Accurately measure out another 30 mL of water and add this to        the bottle. You should always add a total of 90 mL of water        irrespective of the dose prescribed.    -   7. Replace the cap and shake the bottle vigorously for a minimum        of 30 seconds.    -   8. Remove the cap.    -   9. Press the bottle adaptor into the neck of the bottle. The        adaptor is provided so that you can fill the oral syringe with        medicine from the bottle. Replace the cap on the bottle.    -   10. Write the expiration date of the constituted oral suspension        on the bottle label (the expiration date of the constituted oral        suspension is 60 days from the date of constitution).

It is therefore very difficult for a patient or caregiver to prepare theoral suspension by following the above mentioned process and thereforeit has to be prepared by a healthcare provider. Further, suchpreparation is a time consuming process and the patient cannot bebenefited by immediate dose as and when required. The need thereforeexists in the art for the preparation of ready to use, liquidcompositions comprising PDE V inhibitors. Such ready to use, liquidcompositions help in avoiding the time consuming process required forpreparing oral suspension. Further, preparation of oral suspensionrequires expertise (e.g. accurate measuring of water, shaking of thebottle in proper manner, removal of foams & clumps from the suspension)and is therefore difficult for the patient or caregiver to prepare oralsuspension.

Other known compositions comprise excipients which are either additionalfor the formulations or not good when used for human consumption, sayfor example alcohol based formulations. It would therefore be desirableto have liquid compositions of PDE V inhibitors such as sildenafil,tadalafil or pharmaceutically acceptable salts thereof available whichare

Because of their liquid character, liquid compositions represent anideal dosage form for patients who have difficulty swallowing tablets orcapsules. This factor is of particular importance in administration ofdrugs to children and aged patients. The present disclosure is directedto liquid pharmaceutical compositions of PDE V inhibitors. The liquidcompositions of the present disclosure are useful for administering topediatric and geriatric patients. The liquid pharmaceutical compositionsaccording to the present disclosure include liquids, liquid dispersions,suspensions, solutions, emulsions, sprays, spot-on, syrups, elixirs,drops, concentrates and the like.

Most PDE V inhibitors are bitter in taste and are therefore notacceptable to some patient populations such as the pediatric population.Bitter taste of the drugs can be masked by preparing liquid dosage formssuch as solutions or suspensions which comprise sweeteners as well asflavors. Acceptability of dosage forms comprising PDE V inhibitor drugscan thus be increased by increasing its palatability. Therefore, thepresent disclosure provides liquid pharmaceutical compositions of PDE Vinhibitor drugs having palatability.

Liquid dosage forms are designed as ready to use liquids and as powderfor reconstitution into liquid orals like syrups, solutions, suspensionsand emulsions. As discussed in above paragraphs, powder forreconstitution may require skills & expertise and needs to be preparedby a healthcare provider and may not be prepared by the patient orcaregiver. The reconstitution process may also be a time consumingprocess and the patient cannot be benefited by the immediate dose ofdrug as and when required. In such a situation, ready to use, liquidcompositions of PDE V inhibitor drug may be very useful and the patientscan be given required doses immediately using ready to use, liquidcompositions of PDE V inhibitor drug. Therefore, the present disclosureprovides a ready to use, liquid pharmaceutical compositions of PDE Vinhibitor drug.

The solution dosage form can be a viable alternative for patients whohave problems in swallowing the tablet or capsule dosage form. Itprovides assurance of dosage uniformity upon administration to patientsand eliminates difficulty of administration. A solution can also providephysicians more flexibility in designing dosage regimens for patients.Solution dosage form of PDE V inhibitor drug is suitable foradministration to both pediatric and geriatric patients while alsocompensating for a good organoleptic properties and remaining suitablystable. Hence, the development of a liquid formulation is desirablesince it offers improved patient compliance. Embodiments of the presentdisclosure are directed to developing solution dosage forms of PDE Vinhibitor drug. The solution dosage forms according to the presentdisclosure comprises PDE V inhibitor drug or pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable excipients oradditives selected from the group comprising of vehicles,solvents/co-solvents, solubilizers, surfactants, pH adjusting agentsand/or pH modifying agents and/or buffering agents or any combinationthereof. The solution dosage forms according to the present disclosuremay further comprise one or more agents selected from the groupcomprising of preservatives, sweetening agents, flavoring agents andcoloring agents or any combination thereof.

Suspensions possess certain advantages over other liquid dosage forms.Some drugs are insoluble in all acceptable media and must, therefore, beadministered as a tablet, capsule, or as a suspension. In addition,disagreeable tastes can be masked by a suspension of the drug or aderivative of the drug. Drugs in suspension are chemically more stablethan in solution.

Oral administration of drug is considered to be the most important andconvenient method for maximum effectiveness of the drug molecules.Liquid dosage form is the most common and widely accepted dosage formfor having advantages such as faster absorption than solid, palatable,better choice especially for children and old age patients, moreflexibility in achieving the proper dosage of medication and providesease for the patients having difficulty in swallowing other oral dosageforms. Further, pharmaceutical agents are known to have strongbitterness which results into a bitter taste and a feeling of numbnessin the mouth. Therefore oral solid dosage forms are not preferred forsome types of patient population.

An important consideration in any treatment regime is to ensure that thepatient receives the correct dose of medicine. For many patients andmany drugs there is an acceptable dose window that allows fixed-dosemedicines to be used to treat patients with a wide range of body weightswithout the need to precisely adjust the dose. However, there are othergroups of patients where the “fixed-unit-dose” model may not beappropriate, depending on the drug's therapeutic index andpharmacokinetics, e.g. pediatric patients, geriatric patients, patientswith severe renal insufficiency and patients with severe hepaticinsufficiency. Oral solid unit dose forms, e.g. tablets and capsules,are not convenient under such circumstances since they are fixedstrength unit dose forms. In contrast, oral liquid dose forms do havethe in-built flexibility that allows the dose to be tailored to thepatients' needs.

Where the drug is sufficiently soluble, a solution dosage form, e.g. asimple mixture, may be used. But not all drugs are sufficiently solubleto allow suitable strength solution medicines to be developed andmanufactured with an acceptable shelf-life. In such cases, analternative approach could be to develop a stable aqueous suspensionthat will allow consistent dosing of the patient. Pharmaceuticalsuspensions have several advantages and disadvantages when compared toother dosage forms. Since suspensions are liquids, dose adjustment forpatients with renal or hepatic impairment, or for pediatric or geriatricpatients, may be more straightforward. This is an oversimplification ofthe development of a dosing strategy for a drug candidate. There aremany other details that must be considered for a formulation developmentproject to be successful, but it does provide a simple overview of someof the issues.

The suspension must be physically stable (no appreciable settling) for asufficient time, chemically stable over the required time (shelf-life),possess a viscosity that allows it to be used for its intended purpose,be easily reconstituted by shaking, and be acceptable in use to thepatient, care-giver or other user.

Some materials may possess a combination of properties useful in theformulation and manufacture of stable, elegant pharmaceuticalsuspensions. Formulation scientists need to consider the totality ofproperties possessed by a particular excipient. Even though it is beingadded for one particular characteristic, the other properties will stillbe present, and will still influence the formulation.

Many of the recently discovered active pharmaceutical ingredients arequite hydrophobic with limited solubility. They may also be quitedistasteful. Other drugs may also have quite a high chemical degradationprecluding them to be administered as aqueous solutions, and in thiscase, it may be possible to synthesize an insoluble derivative. In othercases, some drugs are required to be present in the gastrointestinaltract or in the pre-corneal pocket with long residence time. For suchdrugs, a suspension is an ideal delivery system as it provides betterchemical stability and larger surface area and is often morebioavailable than aqueous solutions, tablets, and capsules.

Formulation of an elegant, stable, preserved, safe, and effectivesuspension is a technically challenging task compared aqueous solutions,tablets, and capsules. Pharmaceutical suspensions are thermodynamicallyunstable systems. Thus, preparation of such systems is often associatedwith problems of physical stability, content uniformity, sedimentation,caking, re-suspendibility, and crystal growth. Furthermore, issuesrelated to the masking of bitter taste and undesirable odor of thepharmaceutical ingredient must be taken into consideration.

Some desirable attributes of a suspension are described as follows,

-   -   1. It should be safe, effective, stable, and pharmaceutically        elegant during the shelf life of the product.    -   2. The drug should not have a quick sedimentation rate.        Furthermore, it should re-suspend easily upon shaking and it        must not cake.    -   3. Physical attributes such as particle size, particle size        distribution, viscosity should remain fairly uniform throughout        the shelf life of the product.    -   4. Its viscosity must promote free and uniform flow from the        container. The product must have appropriate substantivity that        it spreads freely over the affected area.    -   5. Re-suspension should produce a homogeneous mix of drug        particles such that there is a content uniformity with each        dose.

A quick means to identify whether or not a drug may be more suitable forsolution or suspension is to overlap the pH-stability profile with thepH-solubility profile. This overlap creates a window, which may suggestwhich dosage form might be most desirable and subsequently the type ofexcipients needed.

Oral liquid formulation needs a meticulous blend of ingredients toperform various functions like wetting and solubilization, stabilizationand to impart suitable color, taste and viscosity. The blend should becompatible, non-reactive and stable. The common excipients generallyrequired for any liquid formulation are vehicles (base), viscositybuilders, stabilizers, preservatives, colors and flavors. In addition,solubilizers are required in case of clear liquids, viscosity modifyingagents are needed for suspensions and emulsifying agents for emulsions.

The solution dosage form can be a viable alternative for patients whohave problems in swallowing the tablet or capsule dosage form. Itprovides assurance of dosage uniformity upon administration to patientsand eliminates difficulty of administration. A solution can also providephysicians more flexibility in designing dosage regimens for patients.Solution dosage forms of PDE V inhibitor drugs are suitable foradministration to both pediatric and geriatric patients while alsocompensating for a good organoleptic properties and remaining suitablystable. The development of a liquid formulation is therefore desirablesince it offers improved patient compliance.

Suspensions possess certain advantages over other liquid dosage forms.Some drugs are insoluble in all acceptable media and must, therefore, beadministered as a tablet, capsule, or as a suspension. In addition,disagreeable tastes can be masked by a suspension of the drug or aderivative of the drug. Drugs in suspension are chemically more stablethan in solution.

Liquid dosage forms may be designed as ready to use liquids and aspowder for reconstitution into liquid orals like syrups, solutions,suspensions and emulsions. Powder for reconstitution may require skillsand expertise and, thus, may need to be prepared by a healthcareprovider. The reconstitution process may also be time consuming and thepatient may not be benefited by having the immediate dose of PDE Vinhibitor drug when required. In such a situation, ready to use, liquidcompositions of PDE V inhibitor drug may be very useful and the patientscan be given required doses immediately using ready to use, liquidcompositions of PDE V inhibitor drug.

Liquid Oral Formulations

Embodiments of the present disclosure therefore provide suspensiondosage forms of PDE V inhibitor drug. The suspension dosage formsaccording to the present disclosure comprises PDE V inhibitor drug orpharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients or additives selected from thegroup comprising of vehicles, solvents/co-solvents, solubilizers,viscosity modifying agents, anti-foaming agents, anti-caking agents,wetting agents, surfactants, pH adjusting agents and/or pH modifyingagents and/or buffering agents or any combination thereof. Thesuspension dosage forms according to the present disclosure may furthercomprise one or more agents selected from the group comprising ofpreservatives, sweetening agents, flavoring agents and coloring agentsor any combination thereof.

Embodiments of the present disclosure are directed to providing liquidpharmaceutical compositions of PDE V inhibitor drugs comprising one ormore pharmaceutically acceptable excipients or additives selected fromthe group comprising of vehicles,solvents/co-solvents/solubilizers/solubilizing agents, solubilityenhancing agents, tonicity agents, penetration/permeation enhancers,mucoadhesives, preservatives, pH adjusting agents/pH modifyingagents/buffering agents, surfactants, anti-foaming agents, viscositymodifying agents, bulking agents/auxiliary suspending agents, wettingagents, anti-oxidants, chelating agents, anti-caking agents, sweeteningagents, flavoring agents, coloring agents and the like or anycombination thereof.

In some embodiments, the present disclosure provides liquidpharmaceutical compositions comprising a PDE V inhibitor drug or aderivative thereof and one or more pharmaceutically acceptableexcipients.

As discussed above, because the PDE V inhibitor or derivatives thereofherein have poor wettability (i.e. log P>2.5) in their base form, it isdifficult to make liquid oral compositions of the actives. Accordingly,in some embodiments, the pharmaceutical composition further comprises awetting agent. In some embodiments, the wetting agent is glycerin.

In some embodiments, the pharmaceutical composition is in the form of asuspension for oral delivery. In some embodiments, the pharmaceuticalcomposition is a suspension comprising a PDE V inhibitor and glycerin,wherein the pH of the composition is about 4.0 to about 8.0.Surprisingly, it has been found that use of glycerin as the wettingagent causes the PDE V inhibitor or derivatives thereof to be easilydispersible, without being solubilized, allowing for a stable suspensionto be made. Additionally, it was found that having a buffering agentwhich helped maintain the pH of the formulation at about 4.0 to about8.0 helped reduce the sedimentation rate and lumpiness of theformulation.

In some embodiments, the suspension comprises active pharmaceuticalingredient or a derivative thereof, water, a viscosity modifying agent,a buffering agent in an amount sufficient to make the composition pHabout 4 to about 8, and about 200 mg/mL to about 400 mg/mL glycerin.Exemplary active pharmaceutical ingredients herein may be selected fromsildenafil, tadalafil, and sildenafil citrate.

In some embodiments, the pharmaceutical composition further comprises abuffering agent. In some embodiments, the ratio of glycerin to bufferingagent is about 40:60. In some embodiments, the buffering agent is in anamount sufficient to make the pH of the pharmaceutical composition about4 to about 8.

In some embodiments, the suspension comprises sildenafil or sildenafilcitrate and about 200 mg/mL to about 400 mg/mL glycerin, wherein the pHof the composition is about 4 to about 8. In some embodiments, thesuspension further comprises a buffering agent, a viscosity modifyingagent, a vehicle, and an anti-foaming agent. In some embodiments, thesuspension comprises sildenafil or a derivative thereof, glycerin, abuffering agent, a preservative, a sweetener, an antifoaming agent, aviscosity modifying agent, a flavoring agent and a vehicle.

In some embodiments, the suspensions described herein provide ready touse dosage forms. In some embodiments, the ready to use dosage forms arepalatable and do not require dilution, mixing with other solvents, orfurther manipulation of the composition. It may be appreciated that manyof the actives have been used in parenteral and solid oral medicinalproducts, but have not previously been used in oral liquid preparationsthat were stable over extended periods and that could be retrieved fromthe packaging in a ready to use form as contemplated herein.

In some embodiments, the suspension is room temperature stable. In someembodiments, the pharmaceutical composition requires no reconstitution.In some embodiments, the pharmaceutical compositions may not requireshaking or mixing just prior to use, which is often required withsuspensions.

Suspensions of insoluble drugs may also be used externally, often asprotective agents. Drugs in suspension are chemically more stable thanin solution. This is particularly important with certain drugs where thepharmacist is often called on to prepare such a suspension just prior tothe dispensing of the preparation.

In some embodiments, the liquid pharmaceutical compositions may be inthe form of a liquid dispersion, a suspension, a solution, an emulsion,a spray, a syrup, an elixir, a drop, a concentrate, or a combinationthereof. In some embodiments, the pharmaceutical composition may be inthe form of a dry powder to be prepared into a liquid pharmaceuticalcomposition prior to administration to a patient.

In one of the further embodiments, the present disclosure providesliquid pharmaceutical compositions of PDE V inhibitor drugs in the formof solution dosage forms comprising PDE V inhibitor drug and one or morepharmaceutically acceptable excipients or additives selected from thegroup comprising of vehicles, solvents/co-solvents and/or solubilizers,pH adjusting agents and/or pH modifying agents and/or buffering agentsor any combination thereof. One or more surfactants may also be added inthe solution dosage forms of the present disclosure.

In one of the further embodiments, the present disclosure providesliquid pharmaceutical compositions of PDE V inhibitor drugs in the formof suspension dosage forms comprising PDE V inhibitor drug and one ormore pharmaceutically acceptable excipients or additives selected fromthe group comprising of vehicles, solvents/co-solvents and/orsolubilizers, viscosity modifying agents, anti-foaming agents,surfactants, antioxidants, pH adjusting agents and/or pH modifyingagents and/or buffering agents or any combination thereof. One or moreanti-caking agents may also be added in the suspension dosage forms ofthe present disclosure.

Microbiological contamination presents a significant health hazard inoral liquids. Therefore, the use of preservatives become inevitable toprevent the growth of microorganisms during the product's manufactureand shelf life. Therefore, in one of the further embodiments, the liquidpharmaceutical compositions of the present disclosure may also compriseanti-microbial agents or preserving agents or preservatives.

Increase in the palatability of the drug formulations increases thepatient compliance and patient acceptability towards the drug. In one ofthe further embodiments, the present disclosure therefore providespalatable liquid compositions comprising PDE V inhibitor drug and atleast one or both selected from sweeteners/sweetening agents andflavoring agents.

The liquid compositions according to the present disclosure, withoutlimitation include, aqueous dosage forms, alcoholic and/orhydro-alcoholic dosage forms and non-aqueous dosage forms. Aqueousdosage forms according to the present disclosure may also comprise oneor more non-aqueous and/or organic solvents.

In certain embodiments, the present disclosure provides liquidpharmaceutical compositions of PDE V inhibitor drugs in the form ofsuspensions comprising PDE V inhibitor drug, vehicle(s),solvent(s)/co-solvent(s), solubilizer(s), viscosity modifying agent(s),preservative(s), anti-foaming agent(s), wetting agent(s), surfactant(s),pH adjusting agent(s)/pH modifier(s) or buffering agent(s) or both,sweetener(s) and flavoring agent(s).

In certain embodiments, the present disclosure provides liquidpharmaceutical compositions of PDE V inhibitor drugs in the form ofsolutions comprising PDE V inhibitor drug, vehicle(s),solvent(s)/co-solvent(s), solubilizer(s), preservative(s),surfactant(s), pH adjusting agent(s)/pH modifier(s) or bufferingagent(s) or both, sweetener(s) and flavoring agent(s).

In some of the embodiments, the present disclosure provides the liquidpharmaceutical compositions in the form of spray which may beadministered by oral route or nasal route. Sprays are known by variousnames such as aerosol sprays, liquid pump sprays, or activated mistsetc.

In certain embodiments, the present disclosure provides liquidpharmaceutical compositions of PDE V inhibitor drugs in the form ofspray comprising PDE V inhibitor drug and one or more pharmaceuticallyacceptable excipients selected from the group comprising of vehicles,solvents/co-solvents, solubilizers/solubilizing agents, solubilityenhancing agents, penetration enhancers, mucoadhesives, stabilizingagents, buffering agents/pH adjusting agents/pH modifying agents,tonicity agents, preservatives, viscosity modifying agents, sweeteningagents, flavoring agents and the like or combinations thereof.

In some of the embodiments, the liquid pharmaceutical compositions ofthe present disclosure are in the form of immediate release dosage formsor modified release dosage forms, such as extended release, controlledrelease, sustained release, prolonged release and delayed release. Insome of the embodiments, the liquid pharmaceutical compositions comprisePDE V inhibitor drug and one or more suitable excipients or additivesfor the preparation of modified release dosage forms such as ratecontrolling polymers.

The liquid pharmaceutical compositions of the present disclosure mayalso be prepared by reconstitution of dry powder in suitable diluent ormedia such as water. The dry powder for reconstitution may be in theform of immediate release forms and comprise PDE V inhibitor drug andone or more suitable excipients selected form the group comprising offillers, binders, diluents, disintegrants, pore formers, lubricants,glidants, sweeteners, stabilizing agents, antioxidants, flavoringagents, viscosity modifying agents, surfactants, preservatives andplasticizers. The dry powder for reconstitution may also be in the formof modified release forms and comprise modified release pellets,granules or particles. Such modified release pellets, granules orparticles comprise one or more suitable excipients such as ratecontrolling polymers.

In some embodiments, the liquid pharmaceutical compositions of theinvention are suitable for administration to all types of patients'population. In particular, liquid pharmaceutical compositions of theinvention are suitable for pediatric and geriatric patients. The liquidpharmaceutical compositions of the invention are also useful for thepatients who are unable to take solid oral therapy.

In some embodiments, the pH of the compositions of the presentdisclosure is between about 2.0 and about 11.0. In some of theembodiments, the pH of the compositions is between about 3.0 and about9.0. In some of the embodiments, the pH of the compositions is betweenabout 4.0 and about 8.0. In some of the embodiments, the pH of thecompositions is between about 4.0 and about 6.0. In some of theembodiments, the pH of the compositions is between about 5.0 and about7.0. In some of the embodiments, the pH of the compositions is betweenabout 5.5 and about 6.5.

In one of the further embodiments, the liquid pharmaceuticalcompositions of the present disclosure are stable for prolonged timewhen stored under storage conditions. The term “storage conditions” asused herein without limitation include typical storage conditions suchas 2° C.-8° C., 40° C.±2° C./75±5% RH, 30° C.±2° C./65±5% RH, 25° C.±2°C./40±5% RH, 25° C.±2° C./60±5% RH, and 40° C.±2° C./NMT 25% RH (NMT=notmore than) and accelerated conditions such as 40° C.±2° C./75±5% RH. Theterm “prolonged time” as used herein indicates that the liquidpharmaceutical compositions of the present disclosure are stable for atleast 1 month, at least 3 months, at least 6 months or at least 12months when stored under storage conditions.

In some of the embodiments of the present disclosure, stable liquidpharmaceutical compositions or stability of the liquid pharmaceuticalcompositions refer to compositions which retain at least about 90%, orabout least about 95%, or at least about 96%, or at least about 98%, ofthe labelled concentration of PDE V inhibitor drug contained in the saidcomposition after storage under typical and/or accelerated conditions.In further embodiments, stable liquid pharmaceutical compositions orstability of the liquid pharmaceutical compositions refer to less thanabout 15% (area percent), or less than about 10% (area percent), or lessthan about 7% (area percent), or less than about 5% (area percent), orless than about 2% (area percent) of PDE V inhibitor drug-relatedimpurities are present after storage under typical and/or acceleratedconditions.

In some of the embodiments, liquid pharmaceutical compositions of thepresent disclosure contain no more than about 15% (area percent), or nomore than about 10% (area percent), or no more than about 7% (areapercent), or no more than about 5% (area percent), or no more than about2% (area percent), or no more than about 1% (area percent), or no morethan about 0.5% (area percent), or no more than about 0.2% (areapercent), or no more than about 0.1% (area percent) any known or unknownsingle active pharmaceutical ingredient (PDE V inhibitor drug)-relatedimpurity or other impurity after storage under typical and/oraccelerated conditions.

In some of the embodiments, liquid pharmaceutical compositions of thepresent disclosure contain no more than about 15% (area percent), or nomore than about 10% (area percent), or no more than about 7% (areapercent), or no more than about 5% (area percent), or no more than about2% (area percent), or no more than about 1% (area percent), or no morethan about 0.5% (area percent), or no more than about 0.2% (areapercent), or no more than about 0.1% (area percent) total activepharmaceutical ingredient (PDE V inhibitor drug)-related impurities orother impurities after storage under typical and/or acceleratedconditions.

Methods for determining the stability of the liquid pharmaceuticalcompositions of the present disclosure with respect to a given parameterare well-known to those of skill in the art. For example, individualimpurities and total impurities can be assessed by high-performanceliquid chromatography (HPLC) or thin layer chromatography (TLC). Unlessotherwise indicated to the contrary, a percentage amount of anyindividual impurities (known/unknown), or total impurities reportedherein in the liquid compositions are determined by a peak area percentmethod using HPLC.

All percentages mentioned herein, unless otherwise indicated, are on aw/v basis, i.e. percentage ingredient (active/inactive) present in thetotal volume of the liquid pharmaceutical composition.

In accordance with the methods of use and administration of medicinalproducts, packaging materials, closures and containers vary a great dealand have to meet a wide variety of different requirements. The liquidpharmaceutical compositions of the present disclosure may be packagedwithin any type of pharmaceutically-acceptable package, containers,pumps, bottles with spray pump, bottles with dropper assembly, bottles,collapsible tubes, glass ampoules, stoppered vials, pre-filled syringes,low-density polyethylene (LDPE), high-density polyethylene (HDPE),polyolefin, polypropylene containers/bottles depending upon the quantityof the final dosage form. The bottles or containers without limitationinclude clear/transparent/opaque or amber colored glass bottles orcontainers and clear/transparent/opaque or amber colored plastic bottlesor containers made from polyethylene, polyamide, polycarbonate, acrylicmultipolymers, polypropylene, polyethylene terephthalate, polyvinylchloride, polystyrene and the like. Depending upon the type of thecontainers or bottles, closures may have different shapes and sizes. Theclosure of the packaging material may be made from polyethylene,polyamide, polycarbonate, acrylic multipolymers, polypropylene,polyethylene terephthalate, polyvinyl chloride, polystyrene and thelike.

Liquid pharmaceutical compositions of the present disclosure may bepackaged in a sterile single use bottle/container that contains a unitdose for administration to a patient. Suitable bottles/containers maycontain volumes between 1-10 ml, 10-20 ml, 20-40 ml, and 40-100 ml, andeven more. The container may typically comprise PDE V inhibitor drug inan amount of between 10-40 mg, between 40-80 mg, between 80-130 mg, andeven more. Thus, it may also be noted that the container may be amultiuse container (i.e., retains at least one more unit dose after afirst unit dose is dispensed).

In some of the further embodiments, the present disclosure providesconcentrate liquid compositions which may be diluted using suitablediluent before administering to the patient. In some of the embodiments,the liquid compositions of the invention are ready-to-use liquidcompositions. Such ready-to-use compositions of the invention areadministered directly to the patients in required doses without anyprior preparation e.g. reconstitution in suitable diluent such as water.

Following embodiments of the invention describe suitable excipientswhich may be used to prepare liquid compositions of the presentdisclosure. It is in no way the intention of the presentinventor(s)/applicant(s) to limit the scope of the liquid compositionsof the present disclosure by the description of following embodiments.Described embodiments are for illustrative purpose only and a skilledperson may use other excipients from the same or different classes aswell which may provide liquid compositions of the present disclosuresame or improved physico-chemical properties, palatability, stabilityand the like and retain or increase patients' acceptability towards thetherapy. Such other excipients, classes of excipients and compositionsresulted therefrom are also part of the present disclosure and coveredwithin the scope of the present disclosure.

Vehicles may be used in the liquid compositions of the presentdisclosure. Vehicles are the liquid bases that carry drugs and otherexcipients in dissolved or dispersed state. Vehicles may be aqueous ornon-aqueous or mixture thereof. Non-aqueous solvents/cosolvents may alsobe added in the liquid compositions of the present disclosure toincrease the solubility of poorly soluble substances and enhance thechemical stability of a drug. Suitable solvents/co-solvents,solubilizers or vehicles, that may be employed, in the liquidcompositions of embodiments herein include, but are not limited to,dichloromethane, acetonitrile, ethyl acetate, acetone, propylenecarbonate, water, glycerin, coconut fatty acid diethanolamide, mediumand/or long chain fatty acids or glycerides, monoglycerides,diglycerides, triglycerides, structured triglycerides, soyabean oil,peanut oil, corn oil, corn oil monoglycerides, corn oil diglycerides,corn oil triglycerides, polyethylene glycol,caprylocaproylmacroglycerides, caproyl 90, propylene glycol,polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oilderivatives, castor oil, cottonseed oil, olive oil, safflower oil,peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid,methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutylketone, methyl ethyl ketone and the like or any combinations thereof.

Wetting agents as used herein are routinely used in pharmaceuticalformulations, especially in liquid dosage forms to create a homogeneousdispersion of solid particles in a liquid vehicle. This process can bechallenging due to a layer of adsorbed air on the particle's surface.Hence, even particles with a high density may float on the surface ofthe liquid until the air phase is displaced completely. The use of awetting agent allows removal of adsorbed air and easy penetration of theliquid vehicle into pores of the particle in a short period of time. Foran aqueous vehicle, alcohol, glycerin, and PG are frequently used tofacilitate the removal of adsorbed air from the surface of particles.Whereas for a non-aqueous liquid vehicle, mineral oil is commonly usedas a wetting agent. Non-limiting examples of wetting agents areBenzalkonium chloride, Benzethonium chloride, Cetylpyridinium chloride,Docusate sodium, Nonoxynol 9, Octoxynol, Poloxamer, Poloxamer 124,Poloxamer 188, 237, 338, 407, Polyoxyl 35 castor oil, Polyoxyl 40hydrogenated castor oil, Polyoxyl 10 oleyl ether, Polyoxyl 20cetylstearyl ether, Polyoxyl 40 stearate, Polysorbate 20, Polysorbate40, Polysorbate 60, Polysorbate 80, Sodium lauryl sulfate, Sorbitanmonolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitanmonostearate, Tyloxapol and the like or any combinations thereof.

The amount of wetting agent, e.g. glycerin, is generally about 200 mg/mLto about 400 mg/mL. In some embodiments, the wetting agent is in anamount of about 100 mg/mL to about 1000 mg/mL, about 100 mg/mL to about800 mg/mL, about 100 mg/mL to about 600 mg/mL, about 100 mg/mL to about500 mg/mL, about 100 mg/mL to about 400 mg/mL, about 200 mg/mL to about1000 mg/mL, about 200 mg/mL to about 800 mg/mL, about 200 mg/mL to about600 mg/mL, about 200 mg/mL to about 500 mg/mL, or a value between any ofthese ranges.

Solubility enhancing agents may include, but are not limited to,DL-methionine, caffeine, nicotinamide, vanillin, benzyl alcohol, ethanoland diethylene glycol monoethyl ether and the like or combinationsthereof.

Stabilizing agents may include, but are not limited to, sodiummetabisulphite, sodium bisulphite, ethylene diamine tetraacetic acid(EDTA) or salts thereof, ascorbic acid and the like or combinationsthereof.

Penetration/permeation enhancers may include, but are not limited to,nicotinamide, caffeine, peppermint oil, sodium glycocholate,phospholipids, alkyl saccharides, aprotinin, benzalkonium chloride,ceramides, cetylpyridinium chloride, chitosan,chitosan-4-thiobutylamidine, cyclodextrins, dextran sulfate, dodecylazacycloheptyl-2-ketone, ether lipids (plasmologens), glycerol,glycosylated sphingosines, lauric acid, 23-lauryl ether,lysophosphatidyl choline, menthol, methoxysalicylate, phosphatidylcholine, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine,polycarbophil cysteine, poly-L-arginine, polyoxyethylene,polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, EDTA,sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate,sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodiumtaurodeoxycholate, sodium taurodihydrofusidate, sphingolipids, sterolsand the like or combinations thereof.

Mucoadhesives may also be added in the compositions of the presentdisclosure. Examples of suitable mucoadhesives include, but are notlimited to, hydroxypropyl cellulose, gelatin, crosslinked polyacrylicacid, polymethacrylic acid, polyhydroxyethyl methacrylic acid,hydroxypropyl methyl cellulose, polyethylene glycol, sodiumcarboxymethyl cellulose, hyaluronic acid, chitosan, polycarbophil,pectin, xanthan gum, alginate, copolymers of dextran, polyacrylamide,acacia, copolymer of caprolactone and ethylene oxide, carbopol 934,tragacanth, eudragit and the like or combinations thereof.

The pH of an oral liquid formulation is a key point in many regards.Control of the formulation pH, could prevent large changes duringstorage. Therefore, most formulations utilize a buffer to controlpotential changes in the solution pH. The amount of buffer capacityneeded is generally between 0.01 and 0.1 M, and a concentration between0.05 and 0.5 M is usually sufficient. The selection of a suitable buffershould be based on (i) Whether the acid-base forms are listed for use inoral liquids, (ii) The stability of the drug and excipients in thebuffer, and (iii) The compatibility between the buffer and container. Acombination of buffers can also be used to gain a wider range of pHcompared to the individual buffer alone. However, not all buffers aresuitable for use in oral liquids. For example, a boric acid buffer maybe used for optical and IV delivery but not in oral liquids because ofits toxicity. The stabilizing effect of buffers that have multiplecharged species in solution could also determine the potential reactionbetween excipients and API. For example, buffers that use carbonates,citrate, tartrate, and various phosphate salts may precipitate withcalcium ions by forming sparingly soluble salts. However, thisprecipitation is dependent upon the solution pH. The activity ofphosphate ions may be lowered due to interactions with other solutioncomponents.

In some embodiments, the ratio of glycerin to buffering agent is about40:60. In some embodiments, the ratio of glycerin to buffering agent isabout 50:50, about 55:45, about 65:35, about 70:30, about 75:25, about80:20, about 90:10, about 10:90, about 20:80, about 30:70, about 35:65,about 40:60, or a range between any two of these values.

There are a number of factors that may also affect the solution pH suchas temperature, ionic strength, dilution, and the amount and type ofco-solvents present. For example, the pH of acetate buffers is known toincrease with temperature, whereas the pH of boric acid buffersdecreases with temperature. Finally, the drug in solution may itself actas a buffer. If the drug is a weak electrolyte, such as salicylic acidor ephedrine, the addition of base or acid, respectively, will create asystem in which the drug can act as a buffer.

One of the most crucial factors involved in formulating a pharmaceuticalsuspension is the selection of an appropriate viscosity modifying agent.Viscosity modifying agents, also referred to herein as suspending agentsor thickening agents, impart viscosity, and thus retard particlesedimentation. Other factors considered in the selection of theappropriate agent include desired rheological property, suspendingability in the system, chemical compatibility with other excipients, pHstability, length of time to hydrate, batch-to-batch reproducibility,and cost. Non-limiting examples of pH adjusting agents/modifiers andbuffers are Acetic acid, Adipic acid, Ammonium carbonate, Ammoniumhydroxide, Ammonium phosphate, Boric acid, Citric acid, Diethanolamine,Fumaric acid, Hydrochloric acid, Malic acid, Nitric acid, Propionicacid, Potassium acetate, Potassium bicarbonate, Potassium chloride,Potassium citrate, Potassium metaphosphate, Potassium phosphate, Sodiumacetate, Sodium bicarbonate, Sodium borate, Sodium carbonate, Sodiumchloride, Sodium citrate, Sodium glycolate, Sodium hydroxide, Sodiumlactate, Sodium phosphate, Sodium proprionate, Succinic acid, Sulfuricacid, Tartaric acid, Triethylamine, Triethanolamine, Tromethamine,Trolamine and the like or any combinations thereof.

Viscosity modifying agents can be classified into cellulose derivatives,clays, natural gums, and synthetic gums. In many cases, these excipientsare used in combination. There are many water soluble hydrocolloids thatcan act as viscosity modifying agents in the formulation ofpharmaceutical suspensions. They can be of natural, semi-synthetic orsynthetic origin. Non-limiting examples of viscosity modifying agentsare Acacia, Agar, Alginic acid, Carbomer, Carmellose sodium, Dextrin,Gelatin, Veegum or Gel white, Gellan gum, Sodium alginate,Methylcellulose, Hydroxyethyl cellulose, Hydroxypropyl cellulose, Hydroxypropylmethyl cellulose, Hy droxypropyl starch, Hypromellose,Maltodextrin, Methylcellulose, Modified starch, Pectin, Poloxamer,Polycarbophil, Polyethylene glycol, Polyvinyl acetate, Poly (vinylalcohol), Potassium alginate, Polyvinyl pyrrolidone, Pregelatinizedstarch, Propylene glycol alginate, Sodium alginate, Carboxymethylcellulose or an alkali metal salt thereof, Microcrystalline cellulose,gum Arabic, Karaya gum, Sterculia gum, Tragacanth, Xanthan gum,Bentonite, Carageenan, Guar gum, Colloidal silicon dioxide and the likeor any combinations thereof.

In some embodiments, the viscosity modifying agent is present in anamount of about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about 20mg/mL, about 1 mg/mL to about 15 mg/mL, about 2 mg/mL to about 20 mg/mL,about 2 mg/mL to about 15 mg/mL, about 2 mg/mL to about 10 mg/mL, about2 mg/mL to about 8 mg/mL, about 2 mg/mL to about 6 mg/mL, about 4 mg/mLto about 20 mg/mL, about 4 mg/mL to about 15 mg/mL, about 4 mg/mL toabout 10 mg/mL, about 4 mg/mL to about 8 mg/mL, about 6 mg/mL to about20 mg/mL, about 6 mg/mL to about 15 mg/mL, about 8 mg/mL to about 20mg/mL, about 8 mg/mL to about 15 mg/mL, and any value within theforegoing range.

Although any viscosity modifying agent or agents may be used, in someembodiments, the viscosity modifying agent is xanthan gum and HPMC,which are present at about 2 to about 6 mg/mL, and about 10 mg/mL,respectively. In some embodiments, the buffering agent is citric acidmonohydrate or disodium hydrogen phosphate. Additionally, someembodiments further include microcrystalline cellulose microcrystallinecellulose/sodium carboxymethylcellulose(Avicel), typically at about 20mg/mL.

Microbiological contamination presents a significant health hazard inoral liquids. Therefore, the use of preservatives become inevitable toprevent the growth of microorganisms during the product's manufactureand shelf life, although it may be most desirable to develop a“preservative-free” formulation to address the increasing concerns aboutthe biological activity of these compounds. Most formulations requiresome kind of preservative to ensure no microbial growth.

The majority of preservatives are bacteriostatic rather thanbacteriocidal, and consists of both acid and nonacid types. Among theacidic types are phenol, chlorocresol, 9-phenyl phenol, alkyl esters ofpara-hydroxybenzoic acid, benzoic acid, boric acid, and sorbic acid, andtheir respective salts. Therefore, the pH of solution, and the pKa ofthe preservative need to be carefully evaluated prior to selecting apreservative for a formulation. Neutral preservatives includechlorobutanol, benzyl alcohol, and beta-phenylethyl alcohol. Underalkaline conditions, it is generally regarded that microbial growth isinsignificant and at these pH values, the need for a preservative is notgenerally recommended.

Many preservatives listed in the FDA inactive ingredient guide forliquid dosage forms. Unfortunately, many of them are not recommended foruse in oral liquids and hence the choice of an acceptable preservativefor an oral liquid formulation is limited. In addition, the solubilityof many preservatives in aqueous system may not be high enough foreffective antimicrobial activity. Additionally, it is essential tounderstand that bacteriostatic agents like para hydroxyl benzoic acidscan partition between organic and aqueous phases in a heterogenousliquid formulations in such a way that their activity is significantlyreduced. Non-limiting examples of preservatives are Alcohol, Ethanol,Chlorobutanol, Phenoxyethanol, Potassium benzoate, Benzyl alcohol,Benzoic acid, Potassium sorbate, Sorbic acid, Benzalkonium chloride,Benzethonium chloride, Cetrimonium bromide, Cetylpyridinium chloride,Bronopol, Chlorbutol, Chlorocresol, Cresol, Butylparaben, Methylparaben,Propylparaben, Ethylparaben, Phenol, Thymol, Phenylethanol, Sodiumbenzoate, Antimicrobial solvents like Propylene glycol, Glycerin,Chloroform and the like or any combinations thereof. In addition, someformulation ingredients like nonionic surfactants, quaternary ammoniumcompounds, gelatin, ferric salts, calcium salts and salts of heavymetals, including silver, lead, and mercury prevent microbial growth.

Antioxidants can be compounds that can reduce a drug that has beenoxidized, or compounds that are more readily oxidized than the agentsthey are to protect (oxygen scavengers). Many of the lipid-solubleantioxidants act as scavengers. Antioxidants can also act as chainterminators, reacting with free radicals in solution to stop thefree-radical propagation cycle. Mixtures of chelating agents andantioxidants are often used because there appears to be a synergisticeffect. This occurs because many of the agents act at differing steps inthe oxidative process.

Some substances prone to oxidation include unsaturated oils/fats,compounds with aldehyde or phenolic groups, colors, flavors, sweeteners,plastics and rubbers, the latter being used in containers for products.Oxidation may manifest as products with an unpleasant odour, taste,appearance, precipitation, discoloration or even a slight loss ofactivity. The term rancidity refers to many typical off-flavors thatresult from autoxidation of unsaturated fatty acids that are present inoils and fats, and it affects many oils and fats. The distinct rancidodour may result from short-chain, volatile monomers resulting from thecleavage of the longer chain, less volatile oils and fats. Non-limitingexamples of antioxidants are a-Tocopherol acetate, Ascorbic acid,Erythorbic acid, Butylated hydroxytoluene (BHT), d-a-Tocopherol natural,Monothioglycerol, Sodium bisulfite, Sodium sulfite, Sodiummetabisulfite, Potassium metabisulfite, Acetone sodium bisulfite,Ascorbyl palmitate, Cysteine, d-a-tocopherol synthetic,Nordihydroguaiaretic acid, Sodium formaldehyde sulfoxylate, Sodiumthiosulfate, Acetylcysteine, Ascorbyl palmitate, Butylatedhydroxyanisole (BHA), Cysteine hydrochloride, Dithiothreitol, Propylgallate, Thiourea and the like or any combinations thereof.

In some instances, there are insufficient drug particles in a unit doseof suspension to make a pharmaceutically elegant suspension. This isparticularly true for the more highly active drugs, where the unit doseis small. Under such circumstances, the formulator will need to add moreparticles to improve the appearance of the final product, and also tohelp stabilize the suspension. To serve this purpose, bulking agents,also known as auxiliary viscosity modifying agents are used.Non-limiting examples of bulking agents are Calcium carbonate, Calciumhydroxide, Cellulose, Crospovidone, Dibasic calcium phosphate, Magnesiumcarbonate, Magnesium hydroxide, Microcrystalline cellulose, Silica(silicon dioxide), Titanium dioxide and the like or any combinationsthereof.

Many different materials are capable of adsorbing onto the suspendedparticles, e.g. natural gums, cellulosics and non-ionic surfactants.However, not all of them are able to act as protective colloids andprovide steric hindrance to caking at a sufficiently low concentration.High levels of surfactants, for example, can increase gastro-intestinalmotility. Higher molecular weight gums and cellulosics may also cause anunacceptable increase in the viscosity of the system. There are,however, certain polymers, or grades of polymers, that are capable ofacting as protective colloids at concentrations that do not markedlyincrease the viscosity of the system, or increase gut motility, etc.Such materials include poloxamers, lower molecular weight grades ofpovidone, and low molecular weight grades of some other hydrophiliccolloids.

Surfactant is a general name for materials that possess surfaceactivity; in solution they tend to orient at the surface of the liquid.There are several general classes of surfactants: anionic, cationic,amphoteric and non-ionic. Surfactants are amphiphilic molecules, i.e.part of the molecule is hydrophilic, and part is lipophilic. Thiscombination of the two opposite affinities in the same molecule causesthem to orient to the interface and thereby reduce the interfacialtension between the continuous and disperse phases, such as in emulsionsand suspensions. Ionic surfactants work primarily through electrostaticforces, whereas non-ionic surfactants work primarily through stericforces. Non-limiting examples of surfactants are Sodium lauryl sulfate,Docusate sodium, Cocamidopropyl amino betaine, Polyoxyethylene sorbitanfatty acid esters (Polysorbate, Tween®), Polyoxyethylene 15hydroxystearate (Macrogol 15 hydroxystearate, Solutol HS15®),Polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH 40),Polyoxyethylene stearates (Myrj®), Sorbitan fatty acid esters (Span®),Polyoxyethylene alkyl ethers (Brij®), Polyoxyethylene nonylphenol ether(Nonoxynol®) and the like or any combinations thereof. Anti-foamingagents may be used in the preparation of the liquid pharmaceuticalcompositions of the present disclosure to lower the surface tension andcohesive binding of liquid phase. Non-limiting examples of anti-foamingagents are simethicone, organic phosphates, alcohols, paraffin oils,stearates, glycols and the like or any combinations thereof. In someembodiments, the anti-foaming agent is 30% simethicone emulsion.

Chelating agents, also known as sequestrants, are molecules that havethe ability to form stable complexes with metal ions, particularlydi-valent and tri-valent metal ions including trace metals and heavymetals. These metal ions are often implicated in API degradation byacting as catalysts, e.g. Mg′ will catalyze both ester hydrolysis andthe Maillard interaction between primary or secondary amines andreducing sugars. Oxidative degradation is also often catalyzed by heavymetals. In addition, certain trace metals are required for microbialgrowth, and chelation (sequestration) to form complexes can help preventmicrobial growth and spoilage, and thus allow lower levels ofmicrobiocidal agents to be used. Non-limiting examples of chelatingagents are Calcium disodium edetate, Disodium edetate, Edetic acid (alsoknown as ethylenediaminetetraacetic acid/EDTA), Citric acid and the likeor any combinations thereof.

Palatability of oral medicines is an important factor in compliance.There are several components to palatability including flavor,mouth-feel and sweetness. Most patients prefer medicines that are nottoo bitter but may be slightly “tart” (acidic). Most APIs are bitter.However, for bitterness to develop, the drug must be sufficientlysoluble to interact with taste receptors on the tongue. For insolubleAPIs in the form of suspensions, components of the suspension are alsobitter, e.g. preservatives, or very salty, e.g. buffer systems. However,a slight saltiness and a slight bitterness are desirable forpalatability.

Traditionally, oral medicines were sweetened using Syrup (concentratedsucrose solution) or honey (contains fructose). However, these materialsare inadequate for the formulation of many products because they simplyare not able to adequately mask the very bitter taste of manypharmaceutical materials, including APIs and excipients. Severalalternative sweetening agents have been developed over the years tobetter mask unpleasant tastes in both processed foods andpharmaceuticals.

Several of the materials classified as sweetening agents are sugaralcohols (also known as polyhydric alcohols, polyols and hydrogenatedsugars). Several of the commonly used sweetening agents are ionic andhave the potential to interact with other components of the suspension.Some sweetening agents are more stable than others in aqueous solution.These will be important factors in the final selection of the sweeteningagent. Non-limiting examples of sweetening agents are Glucose,Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose,Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol,Xylitol, Saccharine or the corresponding sodium, potassium or calciumsalt, Cyclamate or the corresponding sodium or calcium salt, Aspartame,or Acesulfame or the potassium salt thereof, Dulcin or Ammoniumglycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidindihydrochalcone, Thaumatin and the like or any combinations thereof.

Flavors are used to improve the palatability of oral medicines. Oneproblem that can arise with oral suspensions is that the suspension mayproduce a “cloying” sensation in the mouth. While this is not the sameas a bitter taste, it can nevertheless cause problems for the patientand affect compliance. This can be a particular problem with high levelsof inorganic components. Flavors can help reduce this “cloying” tasteand thereby improve palatability, and ultimately patient compliance.

There are many different flavors, and most flavors are complex mixturesof many components. Today most flavors are developed by specialistflavor houses, and typically the flavor is formulated for eachindividual application. Since flavor will be part of the suspensioncontinuous phase, it has the maximum potential for interaction, and someflavor components may cause stability issues (physical or chemical) forthe suspension. Flavor development and compounding is a specialistdiscipline. When deciding on which particular flavor is appropriate, theflavor specialist would benefit from knowledge of the other likelycomponents in the suspension, just as the formulation scientist wouldbenefit from knowledge of the components of the flavor. Flavors canadsorb onto finely divided solids, thus reducing their effectiveness.They can also be absorbed by packaging/Flavor preferences vary with age,but the citrus flavors appear generally acceptable to most age groups.Non-limiting examples of flavoring agents are synthetic flavor oils andflavoring aromatics and/or natural oils, extracts from plants leaves,flowers, fruits, and so forth and the like or any combinations thereof.These may include cinnamon oil, oil of wintergreen, peppermint oils,clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil,oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil andthe like or any combinations thereof. Also useful as flavors arevanilla, citrus oil, including lemon, orange, grape, lime andgrapefruit, and fruit essences, including apple, banana, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot, and so forthand the like or any combinations thereof. Solid forms, such as spraydried forms of flavoring agents, may also be useful in the liquidcompositions disclosed herein.

Coloring agents may also be used in the preparation of the liquidcompositions of the present disclosure. Pharmaceutical colors come intwo types; soluble dyes and insoluble pigments. For pharmaceuticalsuspensions intended for oral use, soluble dyes are often used; however,pigments may also be used and would be part of the disperse phase.Soluble dyes have the potential to interact with other components of theformulation.

In some embodiments, the liquid pharmaceutical compositions of thepresent disclosure are non-caking liquid compositions. The term“non-caking” as used herein means that the liquid composition has asmooth consistency and doesn't contain any caking or clumping particles,by visual inspection. Also, the liquid composition in accordance withthe present disclosure does not cake or clump during manufacture, i.e.,when mixed with excipients. Nor does it cake or clump upon storage, evenunder relatively humid conditions, e.g., a relative humidity of about75% or greater and when stored for relatively long periods such as about6 months or longer and even at elevated temperatures of about 40° C. orgreater, or at any combination of such humidity, time and temperatureparameters. Thus, the liquid compositions in accordance with the presentdisclosure will remain non-caking during typical storage and useconditions.

In some embodiments, the PDE V inhibitor may be selected from the groupconsisting of Avanafil, AWD-12-250, BF/GP-385, BMS-22313, BMS-341400,CP-248, CP-461, DA-8 159, Dasantafil, DMPPO, E-4021, E-8010, EMD-82639,EMR-62203, Exisulind, FR-181074, FR-226807, FR-229934, GF-248, KF-31327,KT-734, LAS-34 179, Lusupultide, MJ-12504, NCX-91 1, NM-702, OPC-35564,OSI-461, QAD-171A, Roflumilast, SB-9623 1, SCH-46642, SCH-51866,SCH-59498, Sildenafil, Sildenafil citrate, SK-350, SK-3530, SKF-96231,Sophoflavescenol, SR-265579, T-0156, T-1032, Tadalafil, UK-1 14502, UK-114542, UK-357903, UK-369003, UK-371800, UK-83405, Vardenafil, WIN-65579,WS-63967, YC-1 and Zaprinast, a derivative thereof, and any combinationthereof.

In one of the further embodiments, the liquid pharmaceuticalcompositions of the present disclosure comprise particles of PDE Vinhibitor or a derivative thereof, wherein the d90 of the particles isless than about 1000 microns, or less than about 950 microns, or lessthan about 900 microns, or less than about 850 microns, or less thanabout 800 microns, or less than about 750 microns, or less than about700 microns, or less than about 650 microns, or less than about 600microns, or less than about 550 microns, or less or less than about 200microns, or less than about 150 microns, or less than about 100 microns,or less than about 90 microns or less than about than about 500 microns,or less than about 450 microns, or less than about 400 microns, or lessthan about 350 microns, or less than about 300 microns, or less thanabout 250 microns, or less than about 200 microns, or less than about150 microns, or less than about 100 microns, or less than about 90microns, or less than about 80 microns, or less than about 70 microns,or less than about 60 microns, or less than about 50 microns, or lessthan about 40 microns, or less than about 30 microns, or less than about20 microns, or less than about 10 microns, or less than about 5 microns,or less than about 2 microns, or less than about 1 microns, or less thanabout 0.5 pm.

In one of the further embodiments, the liquid pharmaceuticalcompositions of the present disclosure comprise particles of PDE Vinhibitor or a derivative thereof, wherein the d90 of the particles isless than about 1000 microns, or less than about 950 microns, or lessthan about 900 microns, or less than about 850 microns, or less thanabout 800 microns, or less than about 750 microns, or less than about700 microns, or less than about 650 microns, or less than about 600microns, or less than about 550 microns, or less than about 500 microns,or less than about 450 microns, or less than about 400 microns, or lessthan about 350 microns, or less than about 300 microns, or less thanabout 250 microns, microns, about 90 microns, about 80 microns, about 70microns, about 60 microns, about 50 microns, or less than about 40microns, or less than about 30 microns, or less than about 20 microns,or less than about 10 microns, or less than about 5 microns, or lessthan about 2 microns, or less than about 1 microns, or less than about0.5 microns.

In some embodiments, the d90 of the PDE V particles is about 1000microns, about 950 microns, about 900 microns, about 850 microns, about800 microns, about 750 microns, about 700 microns, about 650 microns,about 600 microns, about 550 microns, about 500 microns, about 450microns, about 400 microns, about 350 microns, about 300 microns, about250 microns, about 200 microns, about 150 microns, about 100 microns,about 90 microns, about 80 microns, about 70 microns, about 60 microns,about 50 microns, about 40 microns, about 30 microns, about 20 microns,about 10 microns, about 5 microns, about 2 microns, about 1 microns,about 0.5 microns, or a range of any two of these values (e.g. about 5microns to about 200 microns, about 1 micron to about 1000 microns,about 1 micron to about 500 microns, about 1 micron to about 200microns, about 5 microns to about 1000 microns, or the like).

In some embodiments, a pharmaceutical composition for oral deliverycomprises a PDE V inhibitor, and a wetting agent. In some embodiments, apharmaceutical composition for oral delivery comprises a PDE Vinhibitor, and a wetting agent, wherein the pH of the composition isabout 4.0 to about 8.0. In some embodiments, a pharmaceuticalcomposition for oral delivery comprises a PDE V inhibitor, a bufferingagent, and a wetting agent. In some embodiments, a pharmaceuticalcomposition in the form of a suspension for oral delivery comprises aPDE V inhibitor, a viscosity modifying agent, a buffering agent, andglycerin. In some embodiments, a pharmaceutical composition in the formof a suspension for oral delivery comprises a PDE V inhibitor, aviscosity modifying agent, a buffering agent in an amount sufficient tomake the composition pH about 4 to about 8; and about 200 mg/mL to about400 mg/mL glycerin.

Methods of Preparation

In one of the embodiments, general formula of the liquid pharmaceuticalcompositions according to the present disclosure may be provided asfollows.

TABLE 1 General formula of liquid pharmaceutical compositions of thepresent disclosure Quantity (% w/v) Sr Solution Suspension No.Ingredient dosage form dosage form 1 Active pharmaceutical ingredient0.01-25 0.01-25 (PDE V inhibitor drug) 2 viscosity modifying agent(s) —0.01-10 3 Preservative(s) 0.01-10 0.01-10 4 Wetting agent(s) —   0-90 5pH adjusting agent(s)/pH Q.S. to adjust Q.S. to adjust modifying agentsthe pH the pH 6 Buffering agent(s) Q.S. to adjust Q.S. to adjust the pHthe pH 7 Solvent(s)/co-solvent(s) Q.S. Q.S. 8 Solubilizer(s) Q.S. Q.S. 9Anti-foaming agent(s) — 0.01-10 10 Anti-caking agent(s) —   0-10 11Antioxidant —   0-10 12 Surfactant(s)   0-10 0.01-10 13 Sweeteningagent(s) 0.01-5 0.01-5 14 Flavoring agent(s) 0.01-5 0.01-5 15 Coloringagent(s)   0-2   0-2 16 Vehicle(s) QS. Q.S. Q.S. = Quantity Sufficient

Those who are skilled in the art will appreciate that different types ofliquid pharmaceutical compositions as described herein can be preparedby using suitable excipients or additives known in the art. Thus, thename of excipients or additives and proportionate range thereof providedin the Table 1 is provided herein for the illustration purpose only andshould not be construed as the exact or the only scope of the presentdisclosure. The liquid pharmaceutical compositions of the presentdisclosure may be prepared using suitable excipients or additives in anysuitable amount.

In one of the further embodiments, the present disclosure providesprocesses for the preparation of the liquid pharmaceutical compositionsof PDE V inhibitor drugs.

Process-1: Preparation of Solution Dosage Forms

-   1. Add one or more sweetener(s) followed by one or more    preservative(s) in the suitable vehicle;-   2. Add PDE V inhibitor drug or salt thereof;-   3. Add one or more buffering agent(s) to adjust the desired pH    followed by flavoring agent; and-   4. Adjust the volume to the required quantity with vehicle.

Process-2: Preparation of Solution Dosage Forms

-   1. Add one or more solvent(s) followed by one or more sweetener(s)    and one or more. preservative(s) in the suitable vehicle;-   2. Add PDE V inhibitor drug or salt thereof;-   3. Add one or more buffering agent(s) to adjust the desired pH    followed by flavoring agent; and-   4. Adjust the volume to the required quantity with vehicle.

Process-3: Preparation of Suspension Dosage Forms

-   1. Add one or more preservative(s) followed by one or more buffering    agent(s) to adjust the desired pH in the suitable vehicle;-   2. Add one or more sweetener(s) and flavoring agent followed by one    or more suitable solvent(s)/co-solvent(s) and/or one or more    solubilizer(s);-   3. Add one or more viscosity modifying agent(s) followed by one or    more anti-foaming agent(s) and one or more surfactant(s);-   4. Add PDE V inhibitor drug or salt thereof; and-   5. Adjust the volume to the required quantity with vehicle.

Process-4: Preparation of Suspension Dosage Forms

-   1. Add and mix one or more solubilizer(s) in the suitable vehicle;-   2. Add one or more viscosity modifying agent(s);-   3. Add one or more antioxidant(s) and one or more sweetener(s)    dissolved in the suitable solvent(s) to step (2);-   4. Add PDE V inhibitor drug or salt thereof; and-   5. Add flavoring agent and adjust the volume to the required    quantity with vehicle.

Process-5: Preparation of Suspension/Solution Dosage Forms

-   1. One or more preservatives are added in the sufficient quantity of    the vehicle;-   2. One or more sweetener, optionally one or more antifoaming agents,    optionally one or more surfactants, one or more solvents/co-solvents    or solubilizers are sequentially added;-   3. PDE V inhibitor drug or salt thereof is added;-   4. Optionally one or more viscosity modifying agents, one or more pH    adjusting agents and/or pH modifying agents and/or buffering agents    (to adjust the pH), optionally one or more solvents/cosolvents and    one or more flavoring agents are added sequentially; and-   5. Required quantity of vehicle is added to make up the volume to    the final quantity.

Process-6: Preparation of Suspension Dosage Forms

-   1. Mix suitable solubilizing agent and solvent;-   2. Add PDE V inhibitor drug or salt or derivative thereof;-   3. Add sufficient quantity of vehicle followed by addition of    flavoring agent; and-   4. Adjust the volume to the required quantity with vehicle.

Process-7: Preparation of Solution/Suspension Dosage Forms

-   1. One or more preservative(s) are added in suitable vehicle;-   2. Optionally one or more buffering agent(s) are added;-   3. Optionally one or more surfactant(s) are added;-   4. PDE V inhibitor drug or salt or derivative thereof is added;-   5. Optionally one or more solvent(s) are added;-   6. Optionally one or more viscosity modifying agent(s) are added;-   7. One or more sweeteners are added followed by addition of    flavoring agent;-   8. Adjust the volume to the required quantity with vehicle.

Process-8: Preparation of Suspension Dosage Form

-   1. Take vehicle(s), buffering agent(s) and preservative(s) one by    one and mix till get dissolved;-   2. Add and mix sweetener(s) and antifoaming agent(s) one by one in    the mixture of step (1) till it gets uniformly dispersed;-   3. Add and mix solvent(s)/co-solvent(s) in the mixture of step (2)    till it gets uniformly dispersed;-   4. Add and mix PDE V inhibitor in the mixture of step (3) till it    gets uniformly dispersed;-   5. Add and mix viscosity modifying agent(s) in the mixture of    step (4) till it gets uniformly dispersed;-   6. Finally add flavouring agent(s) in the mixture of step (5) and    make up the desired volume using vehicle(s) and mix till uniform    suspension is formed.

Process-9: Preparation of Suspension Dosage Form

-   1. Take vehicle(s), buffering agent(s) and preservative(s) one by    one and mix till get dissolved;-   2. Add and mix sweetener(s) as well as antifoaming agent(s) one by    one in the mixture of step (1) till it gets uniformly dispersed;-   3. Add and mix solvent(s)/co-solvent(s) and surfactant(s) one by one    in the mixture of step (2) till it gets uniformly dispersed;-   4. Add and mix PDE V inhibitor in the mixture of step (3) till it    gets uniformly dispersed;-   5. Add and mix viscosity modifying agent(s) in the mixture of    step (4) till it gets uniformly dispersed;-   6. Finally add flavouring agent(s) in the mixture of step (5) and    make up the desired volume using vehicle(s) and mix till uniform    suspension is formed.

Those who are skilled in the art can understand that some variations inthe process described herein can be adopted. A skilled person may omituse of some pharmaceutical excipients as described herein above. Askilled person may also alternatively use some or all pharmaceuticalexcipients as described herein from the same excipient classes. Suchvariations are well within the scope of the present disclosure. Askilled person can also change and/or omit steps of their sequences ofthe herein described process for the purposes of suitability andconvenience where one or more pharmaceutically acceptable excipients mayor may not be used without affecting and diminishing the quality andcharacteristics of the resulting product. Suchvariations/changes/omissions/additions are well within the scope of thepresent disclosure.

The liquid pharmaceutical compositions of the present disclosure mayalso be prepared using processes generally known to those skilled in theart. The processes for the preparation of liquid pharmaceuticalcompositions of the present disclosure may vary depending upon the finaldosage form, e.g. solution, suspension, etc. The processes for thepreparation of the liquid compositions of the present disclosure maycomprise multiple steps. Such steps may include sequential addition ofsuitable excipients/additives. Such steps may also include physicalprocesses for example mixing, stirring, agitation etc.

In one of the embodiments, the present disclosure provides a liquidcomposition comprising Sildenafil or its pharmaceutically acceptablesalts and chemical derivatives such as polymorphs, solvates, hydrates,anhydrous forms, prodrugs, chelates, and complexes thereof and one ormore pharmaceutically acceptable excipients selected from the groupcomprising of vehicles, solvents or co-solvents or solubilizers,viscosity modifying agents or thickening agents or viscosity modifyingagents, anti-foaming agents, stabilizing agents, anti-oxidants, pHadjusting agents or pH modifying agents or buffering agents, wettingagents, bulking agents or auxiliary viscosity modifying agents,chelating agents, surfactants, preservatives, sweetening agents,coloring agents, flavoring agents or combinations thereof.

In one of the embodiments, the present disclosure provides a liquidcomposition comprising Tadalafil or its pharmaceutically acceptablesalts and chemical derivatives such as polymorphs, solvates, hydrates,anhydrous forms, prodrugs, chelates, and complexes thereof and one ormore pharmaceutically acceptable excipients selected from the groupcomprising of vehicles, solvents or co-solvents or solubilizers,viscosity modifying agents or thickening agents or viscosity modifyingagents, anti-foaming agents, stabilizing agents, anti-oxidants, pHadjusting agents or pH modifying agents or buffering agents, wettingagents, bulking agents or auxiliary suspending agents, chelating agents,surfactants, preservatives, sweetening agents, coloring agents,flavoring agents or combinations thereof.

Methods of Treatment

In one of the embodiments, the liquid pharmaceutical compositions of thepresent disclosure are suitable for administration to a subject to treator prevent a disease or a condition. Preferably, the subject is amammal. More preferably, the mammal is a human. Preferably, the diseaseor condition is a disease or condition that is treatable by theadministration of PDE V inhibitor drug as described herein.

In one of the embodiments, the present disclosure is directed to themethod for the treatment of a disease or a condition that can be treatedby PDE V inhibitor drugs comprising administering to a patient, such ashuman, an effective dosage amount of a liquid pharmaceutical compositioncomprising PDE V inhibitor drug and one or more pharmaceuticallyacceptable excipients or additives as disclosed and described herein. Inone of the further embodiments, the present disclosure is directed tothe method for the treatment of at least one disease or conditionselected from the group comprising of hypertension, pulmonaryhypertension, arterial hypertension, pulmonary arterial hypertension,erectile dysfunction, cirrhosis, solid tumor, heart failure, cerebralvasospasm, arthritis, rheumatoid arthritis, atherosclerosis, congenitalheart diseases, parkinsons disease, neonatal encephalopathy,pre-eclampsia, prostate cancer, pancreatic cancer, hepaticencephalopathy, aortic stenosis, cystic fibrosis, peripheral arterialocclusive disease, sickle cell disease, priapism, age-related maculardegeneration, schizophrenia, bronchopulmonary dysplasia, impotence,lymphangioma, dysmenorrhea, urinary incontinence, chronic obstructivepulmonary disease, lymphatic malformations, duchenne muscular dystrophy,becker muscular dystrophy, pulmonary fibrosis, nontuberculousmycobacterial infection, idiopathic pulmonary fibrosis, raynaud'sphenomenon, prostatic hyperplasia, benign prostatic hyperplasiaWaldenstrom's macroglobulinemia and the like comprising administering toa patient, such as human, an effective dosage amount of a liquidpharmaceutical composition comprising PDE V inhibitor drug and one ormore pharmaceutically acceptable excipients or additives as disclosedand described herein.

In one of the further embodiments, the present disclosure is directed touse liquid pharmaceutical compositions of the present disclosure for thetreatment of a disease or a condition that can be treated byadministration of PDE V inhibitor drugs. In one of the furtherembodiments, the present disclosure is directed to use liquidpharmaceutical compositions of the present disclosure for the treatmentof at least one disease or a condition selected from the groupcomprising of hypertension, pulmonary hypertension, arterialhypertension, pulmonary arterial hypertension, erectile dysfunction,cirrhosis, solid tumor, heart failure, cerebral vasospasm, arthritis,rheumatoid arthritis, atherosclerosis, congenital heart diseases,parkinsons disease, neonatal encephalopathy, pre-eclampsia, prostatecancer, pancreatic cancer, hepatic encephalopathy, aortic stenosis,cystic fibrosis, peripheral arterial occlusive disease, sickle celldisease, priapism, age-related macular degeneration, schizophrenia,bronchopulmonary dysplasia, impotence, lymphangioma, dysmenorrhea,urinary incontinence, chronic obstructive pulmonary disease, lymphaticmalformations, duchenne muscular dystrophy, becker muscular dystrophy,pulmonary fibrosis, nontuberculous mycobacterial infection, idiopathicpulmonary fibrosis, raynaud's phenomenon, prostatic hyperplasia, benignprostatic hyperplasia Waldenstrom's macroglobulinemia and the like.

The liquid pharmaceutical compositions of the present disclosure areproposed to have unexpectedly dramatic dissolution profiles. Rapiddissolution of an administered active agent is preferable, as fasterdissolution generally leads to greater bioavailability and faster onsetof action. To improve the dissolution profile and bioavailability of PDEV inhibitor drug it would be useful to increase dissolution of the PDE Vinhibitor drug used so that it could attain a level close to 100%dissolution of the drug substance.

The liquid pharmaceutical compositions of the present disclosurecomprising PDE V inhibitor drug or salt thereof or derivative thereof,exhibit improved or comparable pharmacokinetic profiles as compared tomarketed or known compositions. For example, the Cmax and/or AUC of theliquid pharmaceutical compositions of PDE V inhibitor drug of thepresent disclosure can be greater than or substantially equal to theCmax and/or AUC for known or marketed compositions administered at thesame dose. In addition, the Tmax of the liquid compositions of thepresent disclosure can be lower than or substantially equal to thatobtained for a known or marketed compositions, administered at the samedose. In addition, combinations of an improved or comparable Cmax, AUCand Tmax profile can be exhibited by the liquid compositions of theinvention, as compared to known or marketed compositions. In furtherembodiments, the liquid compositions of the present disclosure mayresult in minimal different absorption levels when administered underfed as compared to fasting conditions.

In one of the embodiments, the liquid compositions of the presentdisclosure exhibit in comparative pharmacokinetic testing with marketedor known formulation, administered at the same dose, a Tmax not greaterthan about 90%, not greater than about 80%, not greater than about 70%,not greater than about 60%, not greater than about 50%, not greater thanabout 30%, not greater than about 25%, not greater than about 20%, notgreater than about 15%, not greater than about 10%, or not greater thanabout 5% of the Tmax exhibited by the marketed or known formulation.

In one of the further embodiments, the liquid compositions of thepresent disclosure exhibit in comparative pharmacokinetic testing withmarketed or known formulation, administered at the same dose, a Cmaxwhich is at least about 50%, at least about 100%, at least about 200%,at least about 300%, at least about 400%, at least about 500%, at leastabout 600%, at least about 700%, at least about 800%, at least about900%, at least about 1000%, at least about 1100%, at least about 1200%,at least about 1300%, at least about 1400%, at least about 1500%, atleast about 1600%, at least about 1700%, at least about 1800%, or atleast about 1900% greater than the Cmax exhibited by the marketed orknown formulation.

In one of the further embodiments, the liquid compositions of thepresent disclosure exhibit in comparative pharmacokinetic testing withmarketed or known formulation, administered at the same dose, an AUCwhich is at least about 25%, at least about 50%, at least about 75%, atleast about 100%, at least about 125%, at least about 150%, at leastabout 175%, at least about 200%, at least about 225%, at least about250%, at least about 275%, at least about 300%, at least about 350%, atleast about 400%, at least about 450%, at least about 500%, at leastabout 550%, at least about 600%, at least about 750%, at least about700%, at least about 750%, at least about 800%, at least about 850%, atleast about 900%, at least about 950%, at least about 1000%, at leastabout 1050%, at least about 1100%, at least about 1150%, or at leastabout 1200% greater than the AUC exhibited by the marketed or knownformulation.

In one of the further embodiments, the Tmax of PDE V inhibitor drug orsalt thereof used for the preparation of the liquid compositionaccording to the present disclosure, when assayed in the plasma of themammalian subject, is less than about 6 to about 8 hours. In otherembodiments of the invention, the Tmax of PDE V inhibitor drug or saltthereof is less than about 6 hours, less than about 5 hours, less thanabout 4 hours, less than about 3 hours, less than about 2 hours, lessthan about 1 hour, or less than about 30 minutes after administration.

In some embodiments, the liquid compositions of the present disclosureexhibit improved or comparable bioavailability as compared to known ormarketed compositions.

Example 1

An exemplary formulation for sildenafil/sildenafil citrate made inaccordance with the embodiments described herein is as follows:

TABLE 2 Sildenafil oral suspension Sr. Role of Prototype Formula No.Ingredients Ingredients % w/v (mg/mL) 1 Sildenafil Active 1 10 2 sodiumbenzoate Preservative 0.2 2 3 Glycerin Wetting agent 40 400 4 SucralosePowder Sweetener 0.5 5 5 30% Simethicone Antifoaming 0.05 0.5 Emulsion 6Citric acid Buffering agent 0.28 2.8 monohydrate 7 Xanthan gum Viscosity0.25 2.5 8 Tri-sodium Buffering agent 0.486 4.8 citrate dihydrate 9Acesulfame K Sweetener 0.1 1 10 Strawberry Flavor Flavor 0.01 0.1 11Water Vehicle q.s to 100 ml q.s to 1 ml

Example 2

An exemplary formulation for tadalafil made in accordance with theembodiments described herein is as follows:

TABLE 3 Tadalafil oral suspension Sr. Role of Prototype Formula No.Ingredients Ingredients % w/v (mg/mL) 1 Tadalafil Active 0.4 4 2 sodiumbenzoate Preservative 0.24 2.4 3 Glycerin Wetting agent 40 400 4Sucralose Powder Sweetener 0.1 1 5 30% Simethicone Antifoaming 0.05 0.5Emulsion 6 Citric acid Buffering agent 0.28 2.8 monohydrate 7 Xanthangum Viscosity 0.25 2.5 8 Tri-sodium Buffering agent 0.486 4.8 citratedihydrate 9 Polysorbate80 Wetting agent 0.1 1 10 Frozen peppermintFlavour 0.01 0.1 flavor 11 Water vehicle q.s to 100 ml q.s to 1 ml0.1% active may also be used with the remaining excipients are at thesame concentration in both strengths

Example 3

Stability testing was performed on the sildenafil suspension of Example1 as outlined in the tables below. The suspension was found to bestable.

TABLE 4 Stability of Sildenafil formulation Specification 40° C./75% 40°C./75% 25° C./60% 25° C./60% Test parameters (shelf life) INITIAL 3M 6M3M 6M Description White to off White to off White to off White to offWhite to off White to off white white white white white white suspensionsuspension suspension suspension suspension suspension Assay of 95-105%99.40% 100% 102.80% 98.6% 98.90% Sildenafil citrate Assay of 80-110%98.10% 97.6% 100.00% 98.4% 98.90% Sodium Benzoate pH 3.5-5.5 4.66 4.764.62 4.74 4.6 Related Substances Sildenafil Not more than ND ND ND ND NDIsobutyl 0.5% analogue [Ph.Eur. Impurity A] Sildenafil N- Not more than0.02% 0.03% 0.01% 0.04% 0.01% oxide [Ph. Eur. 0.30 % Impurity-B] SingleNot more than 0.02% 0.03% 0.02% 0.04% 0.02% maximum 0.2% unknownimpurity Total impurities Not more than 0.00% 0.06% 0.07% 0.07% 0.06%1.0%

Example 4

Stability testing was performed on the tadalafil suspension of Example 2as outlined in the tables below. The suspension was found to be stable.

TABLE 5 Stability of Tadalafil Formulation 40° C./ 25° C./ Testparameters INITIAL 25% 6M 60% 6M Description Off white Off white Offwhite suspension suspension suspension Assay of Tadalafil 101.7% 102.3%101.0% Assay of Sodium 99.60% 102.3% 101.3% Benzoate pH 4.83 5.0 5Related substances by HPLC Unspecified ND 0.01 ND Impurities Totalimpurities ND 0.02 ND

Example 5

A comparison of the dissolution profile of sildenafil formulation havingvarious particle sizes (d90) was performed.

TABLE 6 Sildenafil particle size comparison Test Marketed parametersSpecification product SILL1012 SILL1028 Description White to White WhiteWhite off white suspension suspension suspension suspension DescriptionWhite to White White White off white suspension suspension suspensionsuspension Assay of 95-105% 100.20% 96.90% 101.30% Sildenafil citrateParticle size d(0.1)  0.8  4  1.6 distribution d(0.5)  5.6  19  6.7(Micron) d(0.9) 16.3 127 16.4 Dissolution 10 Min  85.10% 29.50%  77.40%(Mcilvaine 15 Min  93.10% 42.90%  88.30% buffer pH 5.0) 20 Min  96.50%73.80%  91.40% 30 Min 100.30% 89.70%  93.40% 45 Min 101.20% 96.00% 93.60%

Example 6

A comparison of the dissolution profile of tadalafil formulation havingvarious particle sizes (d90) was performed.

TABLE 7 Tadalafil particle size comparison Test Marketed productTIDL3008 TIDL3010 parameters Specification Initial Initial InitialDescription White to Orange, film Off white Off white off white coated,almond suspension suspension suspension shaped tablet Assay of 95-105%100.10% NP 98.40% Tadalafil Particle size d(0.1) NA  9 1 distributiond(0.5) NA 29 3 (Micron) d(0.9) NA 82 8 Dissolution 10 Min  85.90% 36.00%94.50% (0.5% Sodium 15 Min  95.90% 42.00% 95.40% lauryl sulfate) 30 Min‘  99.10% 47.20% 96.70%

It should be understood that various changes and modifications to theembodiments described herein will be apparent to those skilled in theart. Such changes and modifications can be made without departing fromthe spirit and scope of the subject matter of the present disclosure andwithout diminishing its intended advantages. It is therefore intendedthat such changes and modifications be covered within the scope of thepresent disclosure.

1. A liquid oral pharmaceutical composition comprising about 10 mg/mLsildenafil or a pharmaceutically acceptable salt thereof; apharmaceutically acceptable excipient; and a vehicle comprising water;wherein the pharmaceutical composition has a pH of from about 4 to about8.
 2. The liquid oral pharmaceutical composition of claim 1 comprisingsildenafil citrate.
 3. The liquid oral pharmaceutical composition ofclaim 1, wherein the sildenafil comprises particulate sildenafil havinga d90 particulate size of: (i) from about 10 microns to about 200microns, (ii) from about 10 microns to about 100 microns, or (iii) fromabout 20 microns to about 30 microns.
 4. The liquid oral pharmaceuticalcomposition of claim 1, wherein the liquid oral pharmaceuticalcomposition has a pH of: (i) from about 4 to about 6 or (ii) about
 5. 5.The liquid oral pharmaceutical composition of claim 1, wherein thepharmaceutically acceptable excipient comprises a wetting agentcomprising ethanol, glycerin, propylene glycol, or a combinationthereof.
 6. The liquid oral pharmaceutical composition of claim 1,wherein the pharmaceutically acceptable excipient comprises a wettingagent comprising ethanol, glycerin, propylene glycol, or a combinationthereof in an amount of: (i) from about 100 mg/mL to about 1000 mg/mL,(ii) from about 100 mg/mL to about 700 mg/mL, (iii) from about 200 mg/mLto about 600 mg/mL, or (iv) about 400 mg/mL.
 7. The liquid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable excipient comprises a viscosity modifying agent comprising anacacia, an agar, alginic acid, a carbomer, a dextrin, a gelatin, aveegum, a gellan gum, a sodium alginate, a methylcellulose, ahydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxypropylmethylcellulose, a hydroxypropyl starch, a maltodextrin, a methylcellulose, amodified starch, a pectin, a poloxamer, a polycarbophil, a polyethyleneglycol, a polyvinyl acetate, a poly (vinyl alcohol), a potassiumalginate, a polyvinyl pyrrolidone, a pregelatinized starch, a propyleneglycol alginate, a sodium alginate, a carboxymethyl cellulose, an alkalimetal salt of a carboxymethyl cellulose, a microcrystalline cellulose, agum arabic, a karaya gum, a sterculia gum, a tragacanth, a xanthan gum,a bentonite, a carageenan, a guar gum, a colloidal silicon dioxide, or acombination thereof, in an amount of: (i) from about 0.1 mg/mL to about100 mg/mL, (ii) from about 1 mg/mL to about 20 mg/mL, (iii) from about 2mg/mL to about 10 mg/mL, (iv) from about 1 mg/mL to about 6 mg/mL, or(v) from about 2 mg/mL to about 3 mg/mL.
 8. The liquid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable excipient comprises an anti-foaming agent comprising asimethicone, a simethicone emulsion, an organic phosphate, a paraffinoil, a stearate, a glycol, or a combination thereof, in an amount of:(i) from 0.1 mg/mL to about 100 mg/mL, (ii) from about 0.1 mg/mL toabout 0.5 mg/mL, (iii) about 0.15 mg/mL, or (iv) about 0.5 mg/mL.
 9. Theliquid oral pharmaceutical composition of claim 1, wherein thepharmaceutically acceptable excipient comprises a pH adjusting agent, apH modifying agent, or a combination thereof comprising acetic acid,adipic acid, ammonium carbonate, ammonium hydroxide, ammonium phosphate,boric acid, citric acid, diethanolamine, fumaric acid, hydrochloricacid, malic acid, nitric acid, propionic acid, potassium acetate,potassium bicarbonate, potassium citrate, potassium metaphosphate,potassium phosphate, sodium acetate, sodium bicarbonate, sodium borate,sodium carbonate, sodium citrate, sodium glycolate, sodium hydroxide,sodium lactate, sodium phosphate, sodium proprionate, succinic acid,sulfuric acid, tartaric acid, triethylamine, triethanolamine,tromethamine, trolamine, or a combination thereof.
 10. The liquid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable excipient comprises a pH adjusting agent, a pH modifyingagent, or a combination thereof, wherein the pH modifying agentcomprises acetic acid, adipic acid, ammonium carbonate, ammoniumhydroxide, ammonium phosphate, boric acid, citric acid, diethanolamine,fumaric acid, hydrochloric acid, malic acid, nitric acid, propionicacid, potassium acetate, potassium bicarbonate, potassium citrate,potassium metaphosphate, potassium phosphate, sodium acetate, sodiumbicarbonate, sodium borate, sodium carbonate, sodium citrate, sodiumglycolate, sodium hydroxide, sodium lactate, sodium phosphate, sodiumproprionate, succinic acid, sulfuric acid, tartaric acid, triethylamine,triethanolamine, tromethamine, trolamine, or a combination thereof, inan amount of: (i) from about 0.05 M to about 0.5 M, (ii) from about 0.01M to about 0.1 M, or (iii) about 0.03 M.
 11. The liquid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable excipient comprises a preservative, a sweetener, a flavorant,or a combination thereof, wherein the preservative is present in anamount of: (i) from about 0.1 mg/mL to about 100 mg/mL, (ii) from about0.1 mg/mL to about 2.4 mg/mL, or (iii) about 2 mg/mL; wherein thesweetener is present in an amount of: (i) from about 0.1 mg/mL to about50 mg/mL, (ii) from about 0.1 mg/mL to about 6 mg/mL, (iii) from about 1mg/mL to about 6 mg/mL, or (iv) about 6 mg/mL; and wherein the flavorantis present in an amount of: (i) from about 0.1 mg/mL to about 50 mg/mLor (ii) about 0.1 mg/mL.
 12. The liquid oral pharmaceutical compositionof claim 1, wherein the pharmaceutically acceptable excipient comprisesa viscosity modifying agent, a wetting agent, an anti-foaming agent, apH modifying agent, a pH adjusting agent, a preservative, a sweetener, aflavorant, or a combination thereof.
 13. The liquid oral pharmaceuticalcomposition of claim 1, wherein the pharmaceutically acceptableexcipient comprises a viscosity modifying agent in an amount of fromabout 0.1 mg/mL to about 100 mg/mL, a wetting agent in an amount of fromabout 100 mg/mL to about 1000 mg/mL, an anti-foaming agent in an amountof from about 0.1 to about 100 mg/mL, a pH modifying agent in an amountof from about 0.01 M to about 0.5 M, a preservative in an amount of fromabout 0.1 mg/mL to about 100 mg/mL, a sweetener in an amount of fromabout 0.1 mg/mL to about 50 mg/mL, a flavorant in an amount of fromabout 0.1 mg/mL to about 50 mg/mL, or a combination thereof.
 14. Theliquid oral pharmaceutical composition of claim 1, wherein thepharmaceutically acceptable excipient comprises a viscosity modifyingagent in an amount of from about 1 mg/mL to about 20 mg/mL, a wettingagent in an amount of from about 100 mg/mL to about 700 mg/mL, ananti-foaming agent in an amount of from about 0.1 to about 0.5 mg/mL, apH modifying agent in an amount of from about 0.01 M to about 0.1 M, apreservative in an amount of from about 0.1 mg/mL to about 2.4 mg/mL, asweetener in an amount of from about 0.1 mg/mL to about 6 mg/mL, aflavorant in an amount of from about 0.1 mg/mL to about 50 mg/mL, or acombination thereof.
 15. The liquid oral pharmaceutical composition ofclaim 1, wherein the pharmaceutically acceptable excipient comprises aviscosity modifying agent in an amount of from about 1 mg/mL to about 20mg/mL, a wetting agent in an amount of from about 100 mg/mL to about 700mg/mL, an anti-foaming agent in an amount of from about 0.1 to about 0.5mg/mL, a pH modifying agent in an amount of from about 0.01 M to about0.1 M, a preservative in an amount of from about 0.1 mg/mL to about 2.4mg/mL, a sweetener in an amount of from about 0.1 mg/mL to about 6mg/mL, and a flavorant in an amount of from about 0.1 mg/mL to about 50mg/mL, wherein the liquid oral pharmaceutical composition has a pH offrom about 4 to about
 6. 16. The liquid oral pharmaceutical compositionof claim 1, wherein the pharmaceutically acceptable excipient comprisesa viscosity modifying agent comprising in an amount of from about 1mg/mL to about 6 mg/mL, a wetting agent in an amount of from about 200mg/mL to about 600 mg/mL, an anti-foaming agent in an amount of fromabout 0.1 to about 0.5 mg/mL, a pH modifying agent in an amount of fromabout 0.01 M to about 0.1 M, a preservative in an amount of from about0.1 mg/mL to about 2.4 mg/mL, a sweetener in an amount of from about 0.1mg/mL to about 6 mg/mL, a flavorant in an amount of from about 0.1 mg/mLto about 50 mg/mL, or a combination thereof.
 17. The liquid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable excipient comprises a viscosity modifying agent in an amountof from about 1 mg/mL to about 6 mg/mL, a wetting agent in an amount offrom about 200 mg/mL to about 600 mg/mL, an anti-foaming agent in anamount of from about 0.1 to about 0.5 mg/mL, a pH modifying agent in anamount of from about 0.01 M to about 0.1 M, a preservative in an amountof from about 0.1 mg/mL to about 2.4 mg/mL, a sweetener in an amount offrom about 0.1 mg/mL to about 6 mg/mL, and a flavorant in an amount offrom about 0.1 mg/mL to about 50 mg/mL.
 18. The liquid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable excipient comprises a viscosity modifying agent comprisingxanthan gum in an amount of from about 1 mg/mL to about 3 mg/mL, awetting agent comprising glycerin in an amount of from about 200 mg/mLto about 600 mg/mL, an anti-foaming agent comprising a 30% simethiconeemulsion in an amount of from about 0.1 to about 0.5 mg/mL, a pHmodifying agent comprising a citrate buffer, a phosphate buffer, or acombination thereof in an amount of from about 0.01 M to about 0.1 M, apreservative comprising benzoic acid or a salt thereof in an amount offrom about 0.1 mg/mL to about 2.4 mg/mL, a sweetener comprisingsucralose, acesulfame potassium, or a combination thereof in an amountof from about 0.1 mg/mL to about 6 mg/mL, and a flavorant in an amountof from about 0.1 mg/mL to about 50 mg/mL.
 19. The liquid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable excipient comprises a viscosity modifying agent comprisingxanthan gum in an amount of from about 2 mg/mL to about 3 mg/mL, awetting agent comprising glycerin in an amount of about 400 mg/mL, ananti-foaming agent comprising a 30% simethicone emulsion in an amount ofabout 0.5 mg/mL, a pH modifying agent comprising a citrate buffer, aphosphate buffer, or a combination thereof in an amount of from about0.03 M, a preservative comprising benzoic acid or a salt thereof in anamount of from about 0.1 mg/mL to about 2.4 mg/mL, a sweetenercomprising sucralose, acesulfame potassium, or a combination thereof inan amount of from about 0.1 mg/mL to about 6 mg/mL, and a flavorant inan amount of about 0.1 mg/mL.
 20. A method for the treatment of acondition, which comprises administering to a human patient in needthereof a therapeutically effective amount of the liquid oralpharmaceutical composition of claim 1, wherein said condition isselected from the group consisting of pulmonary arterial hypertension,erectile dysfunction, benign prostatic hyperplasia, and a combinationthereof.